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Chatila, T. A., and R. S. Geha. "Phosphorylation of T cell membrane proteins by activators of protein kinase C." Journal of Immunology 140, no. 12 (June 15, 1988): 4308–14. http://dx.doi.org/10.4049/jimmunol.140.12.4308.
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Abstract Activation of the enzyme protein kinase C (PKC) plays an important role in T cell activation. We investigated the phosphorylation of CD2, CD3, CD4, CD5, CD7, CD8, CD28 (Tp44), CD43 (sialophorin, gp115), and LFA-1 after incubation of human PBMC with the (PKC) activator PMA. These proteins were chosen for their role in transmembrane signal transduction (CD2, CD3, CD5, CD28, CD43), cell-cell interaction and adhesion (CD2, CD4, CD8, and LFA-1), or involvement in immunodeficiency states (CD43, CD7). CD5, CD7, CD43, and the alpha-chain of LFA-1 were found to be constitutively phosphorylated. PMA induced rapid hyperphosphorylation of CD5, CD7, and CD43, but not of the LFA-1 alpha-chain, and induced the phosphorylation of CD3, CD4, CD8 and of the LFA-1 beta-chain. PMA did not cause the phosphorylation of CD2 and CD28. PMA-induced phosphorylation was partially inhibited by the PKC inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride. Finally, the T cell activator Con A, which binds to the CD3/TCR complex was shown to induce a profile of protein phosphorylation similar to that observed with PMA. We conclude that PKC-mediated phosphorylation of T cell Ag may represent an important regulatory mechanism that governs the process of T cell activation.
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Зыблева, С. В., and С. Л. Зыблев. "Cluster Analysis of Leukocyte Subpopulations in Kidney Transplantation." Гематология. Трансфузиология. Восточная Европа, no. 2 (November 8, 2021): 168–75. http://dx.doi.org/10.34883/pi.2021.7.2.005.
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Цель. Выявить варианты иммунного реагирования у пациентов при трансплантации почки на основе кластерного анализа, характеризующие течение посттрансплантационного периода. Материалы и методы. Обследовано 104 реципиента почечного трансплантата с терминальной стадией хронической болезни почек, которым выполнена трансплантация аллогенной почки, а также 90 здоровых добровольцев, составивших группу сравнения. Оценены уровни лейкоцитов с использованием метода проточной цитометрии по безотмывочной технологии с использованием моноклональных антител (Beckman Coulter и BD, США) CD4 PС7, CD8 FITC, CD3 PС5.5, CD3 FITC, CD45 PerCP, CD19 APC, CD56+ CD16 PE, CD3 PC5.5, HLA-DR APC, CD38 PE, CD4 FITC, CD3 PC5.5, CD8 APC, CD69 PE, CD127 PЕ, CD25 АРС CD154 PЕ, CD3 APCAF750, IgD FITC, CD27 PC5.5, CD5 APC-AF750, CD40РЕ, CD86 РЕ, CD14 PС7, CD64 FITC, CD86 PЕ LIN PE, CD123 PC7, Anti-HLADR APC-AF750 в объемах, рекомендуемых фирмой-производителем. Результаты и обсуждение. В результате проведенного исследования разработана система оценки иммунного статуса реципиента почечного трансплантата, обеспечивающая персонифицированный мониторинг, анализ и прогнозирование течения посттрансплантационного периода. Описаны виды регуляторных клеточных сетей и их синергический потенциал при трансплантации почки. В основе толерогенного иммунологического комплекса у пациентов после трансплантации почки лежат межклеточные взаимодействия, имеющие иерархическую систему, основа которой представлена кооперацией клеток CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+ и LIN-HLA-DR+CD11c-CD123+. Воснове гиперергического иммунологического комплекса при почечной аллотрансплантации лежат избыточно активированные компоненты иммунного ответа: CD3+CD8+CD69+, CD3+CD4+CD8+, CD3+CD8+CD38+, CD19+CD86+, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD38+, CD14+lowCD86+, и LIN-HLA-DR+CD11c+CD123клетки. Выводы. Выделенные иммунофенотипы позволят осуществить персонифицированный подход к диагностике и лечению пациентов с различными вариантами иммунного реагирования при трансплантации почки. При выявлении иммунофенотипа, соответствующего толерогенному варианту иммунного ответа, терапию пациента в отдаленном посттрансплантационном периоде возможно проводить с учетом низкого иммунологического риска и минимизацией иммуносупрессивной нагрузки. Purpose. To identify the variants of immune response in patients with kidney transplantation on the base of cluster analysis that characterize the course of the post-transplant period. Materials and methods. We examined 104 kidney transplant recipients with end-stage chronic kidney disease, who underwent allograft transplantation, as well as 90 healthy volunteers, who made up the comparison group. Their leukocyte levels were assessed using no-wash flow cytometry with monoclonal antibodies (Beckman Coulter and BD, USA) CD4 PС7, CD8 FITC, CD3 PС5.5, CD3 FITC, CD45 PerCP, CD19 APC, CD56+ CD16 PE, CD3 PC5.5, HLA-DR APC, CD38 PE, CD4 FITC, CD3 PC5.5, CD8 APC, CD69 PE, CD127 PЕ, CD25 АРС CD154 PЕ, CD3 APC-AF750, IgD FITC, CD27 PC5.5, CD5 APC-AF750, CD40РЕ, CD86 РЕ, CD14 PС7, CD64 FITC, CD86 PЕ LIN PE, CD123 PC7, Anti-HLADR APC-AF750 in the volumes recommended by the manufacturer. Results and discussion. As a result of the conducted study, the system for assessing the immune status of a kidney transplant recipient was developed, which provides personalized monitoring, analysis, and prediction of the course of the post-transplant period. The types of regulatory cellular networks and their synergistic potential in kidney transplantation are described. The tolerogenic immunological complex in patients after kidney transplantation is based on intercellular interactions that have a hierarchical system, the base of which is represented by the cooperation of CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+ and LIN-HLA-DR+CD11c-CD123+ cells. The hyperergic immunological complex in renal allotransplantation is based on over-activated components of the immune response: CD3+CD8+CD69+, CD3+CD4+CD8+, CD3+CD8+CD38+, CD19+CD86+, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD38+, CD14+lowCD86+, and LIN-HLA-DR+CD11c+CD123- cells. Conclusion. The detected immunotypes will let to implement the personalized approach to the diagnostics and treatment of patients with various types of immune response in kidney transplantation. If an immunophenotype corresponding to a tolerogenic variant of the immune response is identified, the patient’s therapy in the long-term post-transplant period can be carried out taking into account the low immunological risk and minimizing the immunosuppressive load.
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Zybleva, S. V., and S. L. Zyblev. "Immunological cluster complexes in kidney transplantation." Medical Immunology (Russia) 24, no. 1 (March 10, 2022): 69–80. http://dx.doi.org/10.15789/1563-0625-icc-2212.
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Laboratory tests are significant for the detection of immunopathological disorders in kidney transplantation. As a rule, the choice of tests is carried out individually and is based on the clinical characteristics and the presumptive diagnosis. Most often, in patients after kidney transplantation, atypical and not always standard changes in immunological parameters are observed, which is associated with a combination of many factors leading to different immune responses. All this served as the basis for typing immunological parameters in renal allograft recipients using one of the methods of system analysis – cluster analysis. Kidney transplantation was performed in 104 recipients. Immunological examination was performed on the 360th day after the surgery. The following groups of recipients were identified: KTR1 – with primary graft function on the 7th day and satisfactory graft function within a year, KTR2 – with renal graft dysfunction on the 7th day and within a year. By means of cluster analysis, immunotypes of regulatory complexes were detected and characterized in various courses of the post-transplant period. To assess the immune response in allogeneic kidney transplantation, a set of immune cells with a phenotype should be determined: CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+, LIN-HLA-DR+CD11c-CD123+, CD3+CD8+CD69+, CD3+CD4+CD8+, CD3+CD8+CD38+, CD19+CD86+, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD38+, CD14+lowCD86+, LIN-HLA-DR+CD11c+CD123-. According to our data, the immunological cellular composition of the central point of clustering of the tolerogenic immunological complex is represented by regulatory CD3+CD4+CD25+highCD127+low and double-negative CD3+CD4-CD8-T lymphocytes. The composition of the central point of clustering of the hyperergic immunological complex is represented by the cooperation of CD3+CD8+CD69+ and CD3+CD4+CD8+ cells. The structure of the tolerogenic immune response in patients after kidney transplantation is based on intercellular interactions, which has a hierarchical system, the basis of which is represented by the cooperation of regulatory cells CD3+CD4+CD25+highCD127+low, CD3+CD4-CD8-, CD3+CD4+CD69+, CD3+CD16+CD56+, CD19+CD5+, LIN-HLA-DR+CD11c-CD123+. The hyperergic variant of the immune response in renal allograft transplantation is based on excessive activation of the following links of the immune response: CD3+CD8+CD38+, CD19+CD86+, CD3+CD38+, LIN-HLADR+CD11c+CD123-, CD19+IgD+CD27-, CD3-CD16+CD56+, CD3+CD8+CD69+ and CD14+lowCD86+. The detected immunotypes will make it possible to implement a personalized approach to the diagnosis and treatment of patients with various types of immune response in kidney transplantation.
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Tjønnfjord, G. E., O. P. Veiby, R. Steen, and T. Egeland. "T lymphocyte differentiation in vitro from adult human prethymic CD34+ bone marrow cells." Journal of Experimental Medicine 177, no. 6 (June 1, 1993): 1531–39. http://dx.doi.org/10.1084/jem.177.6.1531.
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Pluripotent lymphohematopoietic stem cells are probably confined to bone marrow cells expressing CD34 surface molecules. To investigate the capacity of adult human CD34+ bone marrow cells to differentiate along the T lymphoid lineage, we plated purified CD34+ cells from healthy adults in liquid culture on adherent thymic stromal cells prepared from HLA- or blood group-mismatched postnatal thymic tissue. We show that purified CD34+CD3-CD4-CD8- bone marrow cells contained progenitors with the ability to differentiate into CD4+ and CD8+ T lymphocytes expressing surface (s)CD3 and T cell receptor alpha/beta in vitro. These progenitors were found in the CD34+CD2+sCD3-CD4-CD8-, CD34+CD7+sCD3-CD4-CD8-, and CD34+CD2+CD7+sCD3-CD4-CD8-, as well as in the CD34+CD2-sCD3-CD4-CD8-, CD34+CD7-sCD3-CD4-CD8-, and CD34+CD2-CD7-sCD3-CD4-CD8- subsets, indicating that T lymphocyte progenitors sensitive to signals mediated by thymic stroma in vitro are not restricted to CD34+ cells already coexpressing early T lymphocyte-associated markers. Finally, we show that T lymphopoiesis was enhanced by c-kit ligand.
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Damle, N. K., and L. V. Doyle. "Stimulation via the CD3 and CD28 molecules induces responsiveness to IL-4 in CD4+CD29+CD45R- memory T lymphocytes." Journal of Immunology 143, no. 6 (September 15, 1989): 1761–67. http://dx.doi.org/10.4049/jimmunol.143.6.1761.
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Abstract Although both IL-2 and IL-4 can promote the growth of activated T cells, IL-4 appears to selectively promote the growth of those helper/inducer and cytolytic T cells which have been activated via their CD3/TCR complex. The present study examines the participation of CD28 and certain other T cell-surface molecules in inducing T cell responsiveness to IL-4. Purified small high density T cells were cultured in the absence of accessory cells with various soluble anti-human T cell mAb with or without soluble anti-CD3 mAb and their responsiveness to IL-4 was studied. None of the soluble anti-T cell mAb alone was able to induce T cell proliferation in response to IL-4. A combination of soluble anti-CD3 with anti-CD28 mAb but not with mAb directed at the CD2, CD5, CD7, CD11a/CD18, or class I MHC molecules induced T cell proliferation in response to IL-4. Anti-CD2 and anti-CD5 mAb enhanced and anti-CD18 mAb inhibited this anti-CD3 + anti-CD28 mAb-induced T cell response to IL-4. In addition, anti-CD2 in combination with anti-CD3 and anti-CD28 mAb induced modest levels of T cell proliferation even in the absence of exogenous cytokines. IL-1, IL-6, and TNF were each unable to replace either anti-CD3 or anti-CD28 mAb in the induction of T cell responsiveness to IL-4, but both IL-1 and TNF enhanced this response. The anti-CD3 + anti-CD28 mAb-induced response to IL-4 was exhibited only by cells within the CD4+CD29+CD45R- memory T subpopulation, and not by CD8+ or CD4+CD45R+ naive T cells. When individually cross-linked with goat anti-mouse IgG antibody immobilized on plastic surface, only anti-CD3 and anti-CD28 mAb were able to induce T cell proliferation. These results indicate that the CD3 and CD28 molecules play a crucial role in inducing T cell responsiveness to IL-4 and that the CD2, CD5, and CD11a/CD18 molecules influence this process.
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Haynes, B. F., and C. S. Heinly. "Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment." Journal of Experimental Medicine 181, no. 4 (April 1, 1995): 1445–58. http://dx.doi.org/10.1084/jem.181.4.1445.
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To determine events that transpire during the earliest stages of human T cell development, we have studied fetal tissues before (7 wk), during (8.2 wk), and after (9.5 wk to birth) colonization of the fetal thymic rudiment with hematopoietic stem cells. Calculation of the approximate volumes of the 7- and 8.2-wk thymuses revealed a 35-fold increase in thymic volumes during this time, with 7-wk thymus height of 160 microM and volume of 0.008 mm3, and 8.2-wk thymus height of 1044 microM and volume of 0.296 mm3. Human thymocytes in the 8.2-wk thymus were CD4+ CD8 alpha+ and cytoplasmic CD3 epsilon+ cCD3 delta+ CD8 beta- and CD3 zetta-. Only 5% of 8-wk thymocytes were T cell receptor (TCR)-beta+, < 0.1% were TCR-gamma+, and none reacted with monoclonal antibodies against TCR-delta. During the first 16 wk of gestation, we observed developmentally regulated expression of CD2 and CD8 beta (appearing at 9.5 wk), CD1a,b, and c molecules (CD1b, then CD1c, then CD1a), TCR molecules (TCR-beta, then TCR-delta), CD45RA and CD45RO isoforms, CD28 (10 wk), CD3 zeta (12-13 wk), and CD6 (12,75 wk). Whereas CD2 was not expressed at the time of initiation of thymic lymphopoiesis, a second CD58 ligand, CD48, was expressed at 8.2 wk, suggesting a role for CD48 early in thymic development. Taken together, these data define sequential phenotypic and morphologic changes that occur in human thymus coincident with thymus colonization by hematopoietic stem cells and provide insight into the molecules that are involved in the earliest stages of human T cell development.
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Abbott, Daniel, Steven Kroft, Maria Hintzke, Luis Carrillo-Polanco, Ashley Cunningham, John Astle, Vasiliki Leventaki, and Alexandra Harrington. "Immunophenotypic Analysis of Peripheral T-Cell Lymphomas: A Single-Center Retrospective Review of Flow Cytometric Analysis." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S109. http://dx.doi.org/10.1093/ajcp/aqz121.012.
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Abstract Background Peripheral T-cell lymphomas (PTCLs) are heterogenous, mature T-cell neoplasms that are a diagnostic challenge, requiring a combination of morphologic assessment and ancillary studies. Flow cytometry (FC) is a tool used routinely in lymphoma diagnosis; however, most analyses are limited to B-cell evaluation and pathologists generally lack experience evaluating for PTCL. We aimed to describe the immunophenotypic aberrancies observed by FC in PTCL. Design PTCLs with FC were collected, excluding primary leukemic processes. Four- and eight-color FC data were reanalyzed with the following antigens (when available): CD2, CD3, CD4, CD5, CD7, CD8, CD30, CD45, CD45RO, CD56, and CD57. Lymphoma cells were compared to normal T cells and an isotype control. Antigen expression was defined as >20%. Results Thirty-eight cases were analyzed (29 males, 9 females, 6-86 years, median 62 years), including 29 PTCLs NOS, 4 angioimmunoblastic T-cell lymphomas (AITLs), 3 anaplastic large cell lymphomas, 1 δγ-TCL, and 1 hepatosplenic TCL from 15 bone marrows, 14 lymph nodes, 6 bloods, 2 fluids, and 1 skin. Twenty cases were CD4+, 4 were CD8+, 3 were dual +, and 10 were dual –. Thirty-seven cases (97%) showed global aberrant antigen patterns, median 4 aberrancies/case (1-8). Lymphoma cells accounted for 0.07% to 68% (median 2.6%) of total events. Aberrant CD7 expression was present in 34 of 38 (89%) and was underexpressed in 22 of 34 (65%). CD3 and CD5 were aberrant in 79% of cases each, with two-thirds showing underexpression. CD2 and CD45RO were aberrant in two-thirds of PTCLs, with overexpression in 61% and 92% of those cases, respectively. One AITL showed no aberrancies. Conclusions Nearly all PTCLs show immunophenotypic aberrancy compared to normal T cells. Most commonly, PTCL showed aberrant underexpression of CD7, CD3, and CD5 and overexpression of CD2 and CD45RO. Our data support FC panels with CD2, CD3, CD4, CD5, CD7, CD8, and CD45RO to optimize recovery of aberrant T cells.
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Akhmatova, E. A., E. V. Sorokina, I. Zh IShubina, E. A. Kurbatova, V. N. Stolpnikova, E. O. Kalinichenko, I. V. Bisheva, and S. A. Skhodova. "Innate immunity cells in a model of acute psoriasis-like inflammation in mice." Russian Journal of Biotherapy 22, no. 4 (November 22, 2023): 43–51. http://dx.doi.org/10.17650/1726-9784-2023-22-4-43-51.
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Background. Experimental animal models of psoriasis helped to clarify the functions of inflammatory mediators, to reveal the contribution of innate or adaptive immune mechanisms, keratinocytes to the development and maintenance of inflammation in psoriasis.Aim. To study the subpopulation composition of immune cells of blood, skin, lymphoid organs and compare two methods of isolation of cells from the skin.Materials and methods. The study included 46 mice of the C57BL / 6 line, which were divided into 2 groups: experimental (n = 24) to reproduce a model of acute psoriasis-like dermatitis using imiquimod cream 5 % (62.5 mg / cm2 / day / mouse, 7 days) and control (n = 22). The severity of skin inflammation was assessed on a point scale. On the 7th day, the skin, spleen, lymph nodes, and thymus were examined. To isolate cells from the skin, the method of spontaneous migration and enzymatic dissociation using collagenase was used. The assessment of the subpopulation structure of mononuclear cells (MNCs) was carried out by flow cytometry using monoclonal antibodies against the corresponding antigens (CD3, CD4, CD5, CD8, MHC class II, TCRyδ, CD38, CD80, CD83, CD86, TLR2). Statistical processing was carried out using the winMDI 2.8 software package.Results. It has been shown that both methods of isolation of skin cells are applicable for immunophenotyping of γδ T-lymphocytes, CD86+, CD83+, CD83+CD86+ dendritic cells. A decrease in TLR2 expression on blood cells and an increase in lymph node and skin cells were revealed. There was a marked increase in the number of CD38+ in the lymph nodes, thymus, and an increase in γδ T-lymphocytes in the lymph nodes and blood. The infiltration of γδ T-lymphocytes, CD8+ is shown in the skin and CD38+ cells.Conclusion. Acute psoriasis-like inflammation of mice was accompanied by an increase in the number of γδ T cells in the blood, lymph nodes and skin. Infiltration of the skin by CD8+ and CD38+ cells was observed. Both methods of cell isolation – the method of spontaneous migration and the method of enzymatic dissociation proved to be applicable for further immunophenotyping.
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Terstappen, LW, S. Huang, and LJ Picker. "Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow." Blood 79, no. 3 (February 1, 1992): 666–77. http://dx.doi.org/10.1182/blood.v79.3.666.bloodjournal793666.
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Using multidimensional flow cytometry we have defined and quantified the human T-cell differentiation pathway, focusing on those events occurring among the most immature thymocytes and putative bone marrow (BM) T-precursors. Early thymocytes were found to express the CD34 antigen and consisted of a mean 1.2% of cells within human pediatric (n = 9) and 2.0% in fetal thymi (n = 4). All CD34+ thymocytes were atypical blast by morphology, expressed intracytoplasmatic, but not cell surface, CD3, and were cell surface CD2+, CD5+, CD7+, CD38+, CD45+, CD45RA+, CD49d+, and LECAM-1(Leu8)high. CD34high thymocytes lacked surface expression of CD4 and CD8, but as CD34 expression diminished there was a coordinate increase in CD4 levels, followed by the appearance of CD8. The expression of CD1 and CD10 also increased concomitant with the loss of CD34, whereas expression of LECAM-1 diminished with CD34 downregulation. The differential expression of these antigens on early thymocytes (as well as the number of thymocytes displaying these patterns) was highly reproducible among the nine pediatric and four fetal specimens examined, suggesting a precise, stereotyped regulation of early differentiation events. Cell populations with antigen expression patterns suggestive of pluripotent stem cell (CD34high, CD38-), or non-T-lineage committed stem cells (CD34+, CD33+ or CD34+, CD19+) were not identified in either fetal or pediatric thymi (sensitivity = 1/10(4)). The presence of cells with the antigenic profile of the earliest CD34+ thymocytes was explored in human BM. Putative BM T-cell precursors with the appropriate phenotype (CD34+, CD7+, CD5+, CD2+, LECAM-1high) were readily identified in fetal specimens (constituting +/- 2% of the CD34+ population), but could not be reliably detected in adults. In contrast with thymi, only 13% of these cells expressed cytoplasmatic CD3, suggesting the presence of the immediate precursor of the putative prothymocyte population. This was further supported by the detection of CD34bright, CD7+, CD2-, CD5-, LECAM-1moderate cells in fetal specimens. Our results document the flow of cell surface differentiation during T-lymphopoiesis and suggest that T-lineage features are first acquired in the BM. The ability to reproducibly identify and isolate T-cell precursor populations of precisely defined maturational stage in marrow and thymus by multiparameter flow cytometry will facilitate characterization of the molecular events controlling T-lineage differentiation.
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Raimondi, SC, FG Behm, PK Roberson, CH Pui, GK Rivera, SB Murphy, and DL Williams. "Cytogenetics of childhood T-cell leukemia." Blood 72, no. 5 (November 1, 1988): 1560–66. http://dx.doi.org/10.1182/blood.v72.5.1560.1560.
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Abstract The karyotypes of 57 cases of childhood T-cell acute lymphoblastic leukemia (ALL) were analyzed to establish the cytogenetic profile in this disease. Three questions were of particular interest. Do the chromosomal changes in T-cell ALL preferentially affect bands where genes encoding the T-cell receptor for antigen (TCR) have been mapped? Do alterations involving the TCR gene regions appear with any notable frequency in B-progenitor ALL? Do chromosomal abnormalities in this disease relate to stage of T-cell ontogeny? A relatively high proportion of cases (65%) had a pseudodiploid karyotype at presentation, the majority (58%) characterized by a translocation. The overall frequency of translocations was 44%, comparable to that among all banded cases of ALL seen in our laboratory. Hypodiploidy and hyperdiploidy were exceedingly rare (only four of 57 cases); 16 cases (28%) had apparently normal karyotypes. In half the cases with a translocation (14 of 24), the breakpoints were in regions to which the alpha and beta chain TCR genes have been mapped. Chromosomal breakpoints that were consistently observed in the vicinity of TCR gene loci were 7q32-q36 (TCR beta chain; n = 8), 14q11-q13 (TCR alpha chain; n = 6); other frequent breakpoints were 9p13-pter (n = 8) and 6q15-qter (n = 9). Chromosomal alterations occurred near TCR gene loci significantly more often in T-cell cases than in a comparison group of 335 patients with B-cell precursor ALL (26% v 1.5%, P = .0001). Stage I thymocyte development (CD7+, CD2+, CD5+, CD1-, CD3-, CD4-, CD8-) was noted in 23 cases, stage II (CD7+, CD2+, CD5+, CD1+, CD3-, CD4 +/-, CD8 +/-) in 25 cases, and stage III (CD9+, CD2+, CD1-, CD5+, CD3+, and either CD4+ or CD8+) in nine cases. The only statistically significant associations between cytogenetic findings and T-cell ontogeny were a higher frequency of normal karyotypes in cases with stage I thymocytes, and of pseudodiploidy in stage II cases. There was no apparent relationship between particular translocations and level of thymocyte maturation. Our findings indicate that most children with T-cell ALL have pseudodiploid karyotypes, although a surprisingly high percentage lack demonstrable abnormal clones. Specific chromosomal changes do not appear to be related to discrete stages of T-cell ontogeny as defined in this study, but they occur preferentially in bands containing TCR genes.
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Raimondi, SC, FG Behm, PK Roberson, CH Pui, GK Rivera, SB Murphy, and DL Williams. "Cytogenetics of childhood T-cell leukemia." Blood 72, no. 5 (November 1, 1988): 1560–66. http://dx.doi.org/10.1182/blood.v72.5.1560.bloodjournal7251560.
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The karyotypes of 57 cases of childhood T-cell acute lymphoblastic leukemia (ALL) were analyzed to establish the cytogenetic profile in this disease. Three questions were of particular interest. Do the chromosomal changes in T-cell ALL preferentially affect bands where genes encoding the T-cell receptor for antigen (TCR) have been mapped? Do alterations involving the TCR gene regions appear with any notable frequency in B-progenitor ALL? Do chromosomal abnormalities in this disease relate to stage of T-cell ontogeny? A relatively high proportion of cases (65%) had a pseudodiploid karyotype at presentation, the majority (58%) characterized by a translocation. The overall frequency of translocations was 44%, comparable to that among all banded cases of ALL seen in our laboratory. Hypodiploidy and hyperdiploidy were exceedingly rare (only four of 57 cases); 16 cases (28%) had apparently normal karyotypes. In half the cases with a translocation (14 of 24), the breakpoints were in regions to which the alpha and beta chain TCR genes have been mapped. Chromosomal breakpoints that were consistently observed in the vicinity of TCR gene loci were 7q32-q36 (TCR beta chain; n = 8), 14q11-q13 (TCR alpha chain; n = 6); other frequent breakpoints were 9p13-pter (n = 8) and 6q15-qter (n = 9). Chromosomal alterations occurred near TCR gene loci significantly more often in T-cell cases than in a comparison group of 335 patients with B-cell precursor ALL (26% v 1.5%, P = .0001). Stage I thymocyte development (CD7+, CD2+, CD5+, CD1-, CD3-, CD4-, CD8-) was noted in 23 cases, stage II (CD7+, CD2+, CD5+, CD1+, CD3-, CD4 +/-, CD8 +/-) in 25 cases, and stage III (CD9+, CD2+, CD1-, CD5+, CD3+, and either CD4+ or CD8+) in nine cases. The only statistically significant associations between cytogenetic findings and T-cell ontogeny were a higher frequency of normal karyotypes in cases with stage I thymocytes, and of pseudodiploidy in stage II cases. There was no apparent relationship between particular translocations and level of thymocyte maturation. Our findings indicate that most children with T-cell ALL have pseudodiploid karyotypes, although a surprisingly high percentage lack demonstrable abnormal clones. Specific chromosomal changes do not appear to be related to discrete stages of T-cell ontogeny as defined in this study, but they occur preferentially in bands containing TCR genes.
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Tamiolakis, Demetrio, Ioannis Venizelos, Athanasia Kotini, Sylva Nikolaidou, and Nikolaos Papadopoulos. "Prevalence of CD8/CD4 Ratio in the Fetal Thymic Parenchyme in Down’s Syndrome." Acta Medica (Hradec Kralove, Czech Republic) 46, no. 4 (2003): 179–82. http://dx.doi.org/10.14712/18059694.2019.30.
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Aim: The maturation of most T- lymphocyte precursors takes place within the meshwork of thymic epithelial cells. Different steps of this process can be defined by immunologic phenotyping. The prothymocytes are positive for the terminal deoxynucleotidyl transferase (TdT) and give rise to cortical thymocytes, which express CD1, CD2, CD3, CD5, and both CD4 and CD8. These CD4 and CD8 double-positive cortical thymocytes differentiate into two lineages: CD4+ or CD8+ lymphocytes of the thymic medulla, by the tenth week of gestation. Our study points towards the determination of the CD8 cytotoxic/suppressor capacity of the fetal thymus in Down’s syndrome. Experimental design: A quantitative comparison of T-lymphocytes (CD3, CD4, and CD8) in the thymic parenchyme in embryos after voluntary abortion during 2nd trimester of gestation and embryos with Down’s syndrome, respectively, was performed. Results: Our results showed: 1) A statistically significant depletion in the total number of T-cells (CD3 positive) in the cases of embryos with Down’s syndrome over those after voluntary abortion, during the second trimester of gestation (p<0.0001, t-test). 2) A significant difference in the CD8/CD4 ratio in the cases of embryos with Down’s syndrome, during the second trimester of gestation which was numerically stronger with the progress of fetal development (20th week: p<0.025; 24th week: p<0.01, chi-square). Conclusions: The occurrence of increased CD8/CD4 ratio in the cases with Down’s syndrome, in the second trimester of gestation, underlines the cytotoxic / suppressor property of the thymus in the affected fetuses.
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Blazar, B. R., A. H. Sharpe, P. A. Taylor, A. Panoskaltsis-Mortari, G. S. Gray, R. Korngold, and D. A. Vallera. "Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells." Journal of Immunology 157, no. 8 (October 15, 1996): 3250–59. http://dx.doi.org/10.4049/jimmunol.157.8.3250.
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Abstract Efficient T cell proliferation requires costimulation via CD28/B7 or other pathways. Graft-vs-host disease (GVHD) is caused by activated donor T cells. We have found that the infusion of anti-B7.1 (CD80) + anti-B7.2 (CD86) mAb is effective in eliminating GVHD lethality induced by either CD8+ or CD4+ T cells. Donor CD4+ and CD8+ T cell expansion was inhibited by almost 100-fold as measured by enumerating thoracic duct lymphocytes (TDL) obtained early post-transplant. TDL retained anti-host responsiveness indicating that not all T cells were anergic. Although anti-CD80 or anti-CD86 mAb individually were ineffective in preventing CD8+ T cell GVHD lethality, each mAb was partially effective in CD4+ T cell-mediated GVHD. Because CD80 expression was found to be up-regulated on donor CD4+ TDL post-transplant, the GVHD capacity of donor CD4+ T cells deficient in CD80 was tested and found to be reduced similarly to that seen with anti-CD80 mAb. These studies demonstrate that anti-CD80 + anti-CD86 mAb infusion is effective in preventing GVHD lethality by inhibiting donor CD4+ or CD8+ T cell expansion and provide the first evidence that CD80 expression on donor T cells is critical for optimal GVHD lethality.
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Distler, Eva, Anna Jürchott, Abdo Konur, Astrid Schneider, Eva M. Wagner, Christoph Huber, Ralf G. Meyer, and Wolfgang Herr. "The CD38-Positive and CD38-Negative Subsets of CD34(high)-Positive Primary Acute Myeloid Leukemia Blasts Differ Considerably in the Expression of Immune Recognition Molecules." Blood 112, no. 11 (November 16, 2008): 2936. http://dx.doi.org/10.1182/blood.v112.11.2936.2936.
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Abstract Acute myeloid leukemia (AML) is thought to arise from a rare putative ‘leukemic stem cell’ that is capable of self-renewal and formation of leukemic blasts. Serial xenotransplantation studies in immunodeficient mice have shown that this leukemia-initiating cell resides at very low numbers within CD34(high)-positive CD38-negative AML cells. Thus, immunotherapeutic approaches successfully eradicating this cell compartment should result in cure from disease. The objective of our study was to characterize the immune phenotype of the CD38-negative and CD38-positive subsets of primary CD34(high)-positive AML blasts ex vivo. We obtained therapeutic leukapheresis products from 17 AML patients of FAB M0-M5 subtypes with white blood cell counts exceeding 10^11/L at primary diagnosis. These products were used to purify CD34-positive cells by immunomagnetic microbeads. CD34(high)-expressing cells were subsequently sorted by flow cytometry into CD38-negative and CD38-positive subsets, respectively. Both fractions were then phenotyped with fluorochrome-conjugated monoclonal antibodies for expression of surface markers previously described to differ between leukemic blasts and stem cells, i.e. CD71 (transferrin receptor), CD90 (Thy-1), CD117 (c-kit receptor), CD123 (IL3Ralpha), CD44, and CD11c. We also included markers relevant for recognition by natural killer cells and T cells, namely HLA class I, HLA-DR, CD40, CD54 (ICAM-1), CD58 (LFA-3), CD80 (B7.1), and CD86 (B7.2), as well as the lineage markers CD2, CD3, CD4, CD7, CD8, CD10, CD14, CD19, CD20, and CD56. Our results demonstrated that the CD38-positive and CD38-negative subsets of CD34(high)-positive AML blasts differed considerably in the expression of CD58, CD71, CD86, CD117, and HLA class I. Although these markers were detected on both subsets, the mean fluorescence intensity (MFI) values were lower in the CD38-negative compartment compared to the CD38-positive counterpart (medians: CD58, 1335 versus 1933; CD71, 657 versus 811; CD86, 746 versus 753; CD117, 490 versus 758; HLA class I, 4431 versus 6000). We compared the MFI values of both cell subsets with the Wilcoxon signed-rank test. P-values below 5% were detected for CD58 (p=0.005), CD71 (p=0.003), CD86 (p=0.041), CD117 (p=0.009), and HLA class I (p=0.011), respectively. The CD38-positive and CD38-negative subsets showed comparable intense staining for CD11c, CD44, CD54, CD123, and HLA-DR. In contrast, CD90, CD80, CD40, and the lineage markers were negative in both fractions. We concluded from these results that primary CD34(high)-positive CD38-negative AML blasts containing small numbers of leukemia-initiating cells expressed overall lower levels of the immune recognition molecules CD58 (LFA-3), CD86 (B7.2), and HLA class I compared to their CD38-positive counterparts. However, all CD34(high)-positive CD38-negative AML cells showed detectable HLA class I expression on the cell surface, making them accessible to T-cell based immunotherapies. In line with previous data, CD71 (transferrin receptor) and CD117 (c-kit receptor) were observed at reduced levels on CD34(high)-positive CD38-negative AML cells. Ongoing functional studies explore if the CD38-negative and CD38-positive subsets of CD34(high)-positive AML blasts differ in the immunogenicity for leukemia-reactive CD4 and CD8 T cells, both in vitro as well as in immunodeficient mice in vivo.
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Barcena, A., MO Muench, AH Galy, J. Cupp, MG Roncarolo, JH Phillips, and H. Spits. "Phenotypic and functional analysis of T-cell precursors in the human fetal liver and thymus: CD7 expression in the early stages of T- and myeloid-cell development." Blood 82, no. 11 (December 1, 1993): 3401–14. http://dx.doi.org/10.1182/blood.v82.11.3401.3401.
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Abstract It has been proposed that the CD7 molecule is the first antigen expressed on the membrane of cells committed to the T-cell lineage during human fetal T-cell ontogeny. To further identify the pre-T cell subpopulation that migrates to the thymus early in ontogeny, we analyzed the phenotypic and functional characteristics of the fetal liver populations separated on the basis of CD7 expression. Three populations expressing different levels of CD7 were observed: CD7bright, CD7dull, and CD7-. A CD7bright population depleted of mature T, B, and myeloid cells (lineage negative, lin-) and mostly composed of CD56+ CD34- natural killer cells did not mature into T cells in a fetal thymic organ culture (FTOC) assay and was devoid of myeloid progenitors in a clonal colony-forming cell assay. In contrast, the CD7-/dull CD34+ lin- populations were capable of differentiating into phenotypically mature T cells after injection into FTOC and contained early myeloid progenitors. Here we phenotypically compared the fetal liver CD7 populations with the most immature fetal thymic subset that differentiated in the FTOC assay, namely the triple negative (TN, CD3- CD4-CD8-) thymocytes. Fetal TN lin- expressed high levels of CD34 marker and were further subdivided by their expression of CD1 antigen, because CD1- TN thymocytes express higher levels of CD34 antigen compared with CD1+ TN cells. CD1- lin -TN thymocytes are characterized by expressing high levels of CD2, CD7, and CD34 markers and dull levels of CD5, CD10, and CD28 molecules. We could not find fetal liver pre-T cells with a phenotype equivalent to that of TN thymocytes. Our data show that CD7 does not necessarily identify T-cell precursors during fetal T-cell development and strongly support the hypothesis that the acquisition of early T-cell markers as CD2, CD28, and CD5 molecules on the cell surface of T-cell progenitors takes place intrathymically.
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Barcena, A., MO Muench, AH Galy, J. Cupp, MG Roncarolo, JH Phillips, and H. Spits. "Phenotypic and functional analysis of T-cell precursors in the human fetal liver and thymus: CD7 expression in the early stages of T- and myeloid-cell development." Blood 82, no. 11 (December 1, 1993): 3401–14. http://dx.doi.org/10.1182/blood.v82.11.3401.bloodjournal82113401.
Full textAbstract:
It has been proposed that the CD7 molecule is the first antigen expressed on the membrane of cells committed to the T-cell lineage during human fetal T-cell ontogeny. To further identify the pre-T cell subpopulation that migrates to the thymus early in ontogeny, we analyzed the phenotypic and functional characteristics of the fetal liver populations separated on the basis of CD7 expression. Three populations expressing different levels of CD7 were observed: CD7bright, CD7dull, and CD7-. A CD7bright population depleted of mature T, B, and myeloid cells (lineage negative, lin-) and mostly composed of CD56+ CD34- natural killer cells did not mature into T cells in a fetal thymic organ culture (FTOC) assay and was devoid of myeloid progenitors in a clonal colony-forming cell assay. In contrast, the CD7-/dull CD34+ lin- populations were capable of differentiating into phenotypically mature T cells after injection into FTOC and contained early myeloid progenitors. Here we phenotypically compared the fetal liver CD7 populations with the most immature fetal thymic subset that differentiated in the FTOC assay, namely the triple negative (TN, CD3- CD4-CD8-) thymocytes. Fetal TN lin- expressed high levels of CD34 marker and were further subdivided by their expression of CD1 antigen, because CD1- TN thymocytes express higher levels of CD34 antigen compared with CD1+ TN cells. CD1- lin -TN thymocytes are characterized by expressing high levels of CD2, CD7, and CD34 markers and dull levels of CD5, CD10, and CD28 molecules. We could not find fetal liver pre-T cells with a phenotype equivalent to that of TN thymocytes. Our data show that CD7 does not necessarily identify T-cell precursors during fetal T-cell development and strongly support the hypothesis that the acquisition of early T-cell markers as CD2, CD28, and CD5 molecules on the cell surface of T-cell progenitors takes place intrathymically.
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Blue, M. L., J. F. Daley, H. Levine, K. R. Branton, and S. F. Schlossman. "Regulation of CD4 and CD8 surface expression on human thymocyte subpopulations by triggering through CD2 and the CD3-T cell receptor." Journal of Immunology 142, no. 2 (January 15, 1989): 374–80. http://dx.doi.org/10.4049/jimmunol.142.2.374.
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Abstract Human thymocytes bearing the CD4 and/or CD8 antigens can be fractionated into cells with an immature and more mature phenotype based on their quantitative expression of the CD3 Ag (J. Immunol. 138:3108; J. Immunol. 139:1065). We show that the expression of CD4 and CD8 on thymocyte subpopulations with low CD3 (CD3L) and high CD3 (CD3H) is regulated by activation through the CD2 molecule and perturbation of the CD3-T cell receptor complex (CD3-Ti). Similar to its previously reported effects on peripheral T cells, PMA was able to induce the down-regulation of surface CD4, but not CD8, on thymocyte subpopulations. PMA could induce CD4 and CD8 phosphorylation in both CD3L and CD3H fractions. These results suggest that if changes in phosphorylation represent the mechanism by which CD4 and CD8 are able to transmit signals, this mechanism is operative in both CD3L and CD3H subpopulations. Treatment with anti-T11(2) and anti-T11(3) antibodies (CD2 activation pathway) resulted in partial down-regulation of CD4 but not CD8 surface expression on both CD3L and CD3H thymocytes. Similar treatment had no detectable effect on peripheral T cells. The down-regulation of surface CD4 induced by activation via CD2 could be inhibited by treatment of thymocytes with anti-CD3 antibodies. Treatment of thymocytes with anti-CD3 alone or following CD2 activation induced the selective down-regulation of surface CD8 within 15 minutes. These results suggest that CD2 and CD3-Ti triggering may regulate CD4 and CD8 surface expression on thymocytes. Furthermore, these results suggest that "cross-talk" between the CD2 and CD3-Ti pathway of activation may involve CD4 and CD8 molecules.
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Parra, E., A. G. Wingren, G. Hedlund, T. Kalland, and M. Dohlsten. "The role of B7-1 and LFA-3 in costimulation of CD8+ T cells." Journal of Immunology 158, no. 2 (January 15, 1997): 637–42. http://dx.doi.org/10.4049/jimmunol.158.2.637.
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Abstract This study compares the ability of LFA-3 (CD58) and B7-1 (CD80) ligands to provide costimulatory signals for superantigen (SAg)-stimulated CD8+ and CD4+ T cells. We show that B7-1 and LFA-3 costimulation activate CD8+ T cells to proliferation, cytokine production (IL-2, TNF, and IFN-gamma), and cytotoxicity. A long-lasting proliferative response was observed after combined DR/B7-1/LFA-3 costimulation. Detailed analysis of SEA-activated CD8+ T cells revealed that maximal production of IFN-gamma was seen in LFA-3-costimulated cells, while production of IL-2 was mainly induced after B7-1 costimulation. A fivefold increase in the IFN-gamma production was observed when activated CD8+ T cells were costimulated with Chinese hamster ovary (CHO)-DR/LFA-3 cells compared with the secretion induced by CHO-DR/B7-1. In contrast, SEA-treated CD4+ T cells costimulated with B7-1 or LFA-3 gave rise to a similar production of IFN-gamma, suggesting a preferential function for the CD2/LFA-3 pathway in the regulation of IFN-gamma in CD8+ T cells. Moreover, the generation of CTL was supported similarly by B7-1 and LFA-3 costimulation, but not by CHO-DR cells. We conclude that ligation of the CD28 and CD2 receptors mediate distinct effect on CD8+ and CD4+ T cell effector functions.
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Terstappen, LW, S. Huang, and LJ Picker. "Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow." Blood 79, no. 3 (February 1, 1992): 666–77. http://dx.doi.org/10.1182/blood.v79.3.666.666.
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Abstract Using multidimensional flow cytometry we have defined and quantified the human T-cell differentiation pathway, focusing on those events occurring among the most immature thymocytes and putative bone marrow (BM) T-precursors. Early thymocytes were found to express the CD34 antigen and consisted of a mean 1.2% of cells within human pediatric (n = 9) and 2.0% in fetal thymi (n = 4). All CD34+ thymocytes were atypical blast by morphology, expressed intracytoplasmatic, but not cell surface, CD3, and were cell surface CD2+, CD5+, CD7+, CD38+, CD45+, CD45RA+, CD49d+, and LECAM-1(Leu8)high. CD34high thymocytes lacked surface expression of CD4 and CD8, but as CD34 expression diminished there was a coordinate increase in CD4 levels, followed by the appearance of CD8. The expression of CD1 and CD10 also increased concomitant with the loss of CD34, whereas expression of LECAM-1 diminished with CD34 downregulation. The differential expression of these antigens on early thymocytes (as well as the number of thymocytes displaying these patterns) was highly reproducible among the nine pediatric and four fetal specimens examined, suggesting a precise, stereotyped regulation of early differentiation events. Cell populations with antigen expression patterns suggestive of pluripotent stem cell (CD34high, CD38-), or non-T-lineage committed stem cells (CD34+, CD33+ or CD34+, CD19+) were not identified in either fetal or pediatric thymi (sensitivity = 1/10(4)). The presence of cells with the antigenic profile of the earliest CD34+ thymocytes was explored in human BM. Putative BM T-cell precursors with the appropriate phenotype (CD34+, CD7+, CD5+, CD2+, LECAM-1high) were readily identified in fetal specimens (constituting +/- 2% of the CD34+ population), but could not be reliably detected in adults. In contrast with thymi, only 13% of these cells expressed cytoplasmatic CD3, suggesting the presence of the immediate precursor of the putative prothymocyte population. This was further supported by the detection of CD34bright, CD7+, CD2-, CD5-, LECAM-1moderate cells in fetal specimens. Our results document the flow of cell surface differentiation during T-lymphopoiesis and suggest that T-lineage features are first acquired in the BM. The ability to reproducibly identify and isolate T-cell precursor populations of precisely defined maturational stage in marrow and thymus by multiparameter flow cytometry will facilitate characterization of the molecular events controlling T-lineage differentiation.
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Suda, T., and A. Zlotnik. "In vitro induction of CD8 expression on thymic pre-T cells. II. Characterization of CD3-CD4-CD8 alpha + cells generated in vitro by culturing CD25+CD3-CD4-CD8- thymocytes with T cell growth factor-beta and tumor necrosis factor-alpha." Journal of Immunology 149, no. 1 (July 1, 1992): 71–76. http://dx.doi.org/10.4049/jimmunol.149.1.71.
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Abstract We previously reported that CD25 (IL-2R p55)-positive CD3-CD4-CD8- murine thymocytes can be induced to express CD8 alpha (Lyt-2) by transforming growth factor-beta plus TNF-alpha in the presence of IL-7 (which is necessary to maintain the viability and differentiation capacity of CD25+CD3-CD4-CD8- thymocytes in vitro). The majority of cells recovered after 2 to 3 days from these cultures expressed CD8 alpha (but not CD3 or CD4). In this study, we have characterized these in vitro generated CD3-CD4-CD8 alpha + thymocytes and compared them with normal CD3-CD4-CD8+ thymocytes. Unlike normal CD3-CD4-CD8+ thymocytes that express CD8 alpha and CD8 beta (Lyt-3-chain) simultaneously, only a fraction of in vitro generated CD3-CD4-CD8 alpha + cells expressed CD8 beta. However, along with the induction of CD8 alpha and CD8 beta expression, the expression of other T cell differentiation markers (including CD2, CD25, and CD44) also changed in a manner corresponding to physiologic differentiation. Cell-surface phenotyping suggests that CD8 alpha + beta - cells are less mature than CD8 alpha + beta + cells. These in vitro generated CD3-CD4-CD8 alpha + thymocytes expanded and differentiated into the CD4+CD8+ stage as well as mature (CD3+) single positive (CD4+CD8-) and CD4-CD8+) stages in fetal thymus organ culture that had been depleted of lymphoid cells by treatment with 2-deoxyguanosine. The latter observation indicates that these in vitro generated CD3-CD4-CD8 alpha + thymocytes are responsive to other differentiation-inducing signals (including those that induce CD4) that exist in fetal thymus organ culture. These results suggest that in vitro generated CD3-CD4-CD8 alpha + thymocytes represent intermediate differentiation stages between CD25+CD3-CD4-CD8- and CD3-CD4-CD8+ cells found in normal thymus.
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Vandekerckhove, B. A., J. F. Krowka, J. M. McCune, J. E. de Vries, H. Spits, and M. G. Roncarolo. "Clonal analysis of the peripheral T cell compartment of the SCID-hu mouse." Journal of Immunology 146, no. 12 (June 15, 1991): 4173–79. http://dx.doi.org/10.4049/jimmunol.146.12.4173.
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Abstract Severe combined immunodeficiency (SCID) mice can be transplanted successfully with human fetal liver and thymus (SCID-hu mice). Precursor cells derived from the fetal liver differentiate in the thymus and migrate into the blood as mature T cells. In the present paper, the peripheral T cell compartment of such mice was studied. Peripheral WBC were activated by PHA and cultured in the presence of irradiated human feeder cells. The resultant cell population consisted exclusively of human CD1- CD2+ CD3+ CD7+ T lymphocytes; up to 4% of the T cells expressed the TCR gamma delta, whereas 95 to 100% were TCR alpha beta +. The CD4bright (42 to 66%) and CD8bright (30 to 54%) populations coexpressed variable but low levels of CD8 and CD4, respectively. The T cell cultures from the SCID-hu mice did not display reactivity towards the autologous human EBV-transformed B cell lines (B-LCL). On the other hand, these human T cells proliferated and were cytotoxic against allogeneic human B-LCL. T cell clones were established from cultured SCID-hu T cells. All T cell clones were TCR alpha beta + CD3+ CD2+; 61% of the clones were CD4+ CD8-, 27% were CD8+ CD4-, 11% were CD8+ CD4lo, and 2% were CD4+ CD8lo. None of these clones recognized the autologous B-LCL established from the fetal human donor. Fourteen of 100 T cell clones had specific alloreactivity, as tested on a panel of five B-LCL. Of these 14, two CD8+ CD4lo and two CD8+ CD4- clones were cytotoxic and did not proliferate in response to specific stimulator cells. Furthermore, two CD4+ CD8lo and eight CD4+ CD8- clones proliferated specifically in response to alloantigens. In conclusion, the peripheral human T cells of SCID-hu animals are functional and their TCR repertoire is polyclonal, alloreactive, and devoid of self-reactive cells. Therefore, the SCID-hu mouse can be a suitable model for the study of alloreactivity and allotolerance in vivo, as well as for the study of negative selection in the human thymus.
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Giraldo, Nicolas, Natalia Bolaños, Adriana Cuellar, Nubia Roa, Zulma Cucunubá, Victor Velasco, Fernando Rosas, Concepción Puerta, and John González. "Proliferative dysfunction in chronically activated T lymphocytes from chagasic patients (70.1)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 70.1. http://dx.doi.org/10.4049/jimmunol.188.supp.70.1.
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Abstract Background: Trypanosoma cruzi persistence has been associated with cardiac and gastrointestinal tissue damage in nearly 30% of the infected individuals; however, the pathogenic mechanisms are yet unknown. This study’s goal was to compare the activation status and proliferative capacity of T lymphocytes among chronic chagasic patients and uninfected controls. Methodology: Twenty-seven chronic chagasic patients, 20 healthy individuals and 28 non-chagasic cardiomyopathy donors were analyzed. Peripheral blood cells were stained with CD3, CD4, CD8, CD28, HLA-DR and CD38. PBMCs were labeled with CFSE and co-cultivated with PHA or T. cruzi lysate; at the fifth day post-stimulation cells were stained for CD3, CD4 and CD8. Results: Chagasic patients displayed higher frequencies of CD4+ (P=0.0001) and CD8+ (P=0.0002) T cells co-expressing HLA-DR and CD38 in comparison with healthy and non-chagasic cardiomyopathy donors. Also, the former group exhibited lower percentages of CD8+/CD28+ T lymphocytes (P=0.0005). After 5 days of stimulation, the proliferation index was lower in both CD4+ (P=0.01) and CD8+ (P=0.04) PHA-stimulated T cells from chagasic donors when compared with both control groups. Conclusions: Despite their increased activation status, the T lymphocytes from chagasic donors displayed reduced proliferative capacity after mitogenic stimulation, corroborating a dysfunctional cellular immune response in the chronic stages of the disease.
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He, Guangsheng, Ling Zhou, De Pei Wu, Aining Sun, and Miao Miao. "CD4+Treg in Immune Pathophysiology of Aplastic Anemia." Blood 108, no. 11 (November 16, 2006): 3768. http://dx.doi.org/10.1182/blood.v108.11.3768.3768.
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Abstract Objective: To explore the possible immune pathophysiology of CD4+T regulatory (CD4+Treg) in acquired aplastic anemia (AA). Methods: According to the markers on membrane, cytokines, and effective mechanisms of CD4+Treg, the levels of CD4+CD25+Treg,CD4+CTLA-4+Treg,CD4+ICOS+Treg,CD4+PD-1+Treg,CD3+CD8−IL-10+Treg,CD3+CD8−TGF-β1+Treg,CD3+CD8−IL-Treg in the bone marrow of 23 cases with AA at active phase, 10cases with AA at recovery phase, 15 normal controls, were measured, and the relationship between CD4+Treg and priming immune factor-CD28 or effective immune factor-IFN-γ were also evaluated respectively. Results: [circ1]In the group of AA at active phase, at recovery phase, and normal controls, CD4+CD25+Treg: (3.36±2.05)%, (3.49±1.71)%, (2.40±0.77)%, CD4+CTLA-4+ Treg: (1.43±0.67)%, (3.46±2.26)%, (2.45±1.30)%, CD4+ICOS+Treg: (2.04±1.79)%, (2.95±2.23)%, (2.37±1.68)%, CD4+PD-1+Treg: (1.40±1.32)%, (2.34±0.87)%, (2.07±1.64)%, CD3+CD8−IL-10+Treg: (2.14±1.19)%, (2.37±1.20)%, (2.04±1.25)%, CD3+CD8−TGF-β1+Treg: (1.83±0.99)%, (1.52±0.73)%, (2.15±1.17)%, CD3+CD8−IL-4+Treg: (2.46±1.65)%, (2.53±1.61)%, (1.99±1.27)%; costimulatory of CD3+CD4+CD28+ was: (39.84±10.89)%, (22.72±9.08)%, 31.40±10.83)%, the Th1cells CD3+CD8−IFN-γ+ were: (11.13±4.96)%, (5.39±4.29)%, (4.21±2.11)%. [circ2] Contrast to normal controls, while CD4+CTLA-4+Treg of AA at active phase deceased markedly (p=<0.01), levels of other CD4+Treg which marked by membrane moleculars or cytokines: CD4+CD25+Treg, CD4+PD-1+Treg, CD4+ICOS+Treg, CD3+CD8−IL-10+Treg, CD3+CD8−TGF-β1+Treg, CD3+CD8−IL-4+Treg did not change significantly (p>0.05); [circ3] Contrast to normal controls, the ratio of membrane costimulatory of CD28/ICOS CD28/CTLA-4, CD28/PD-1 were all increased significantly (p<0.05) in AA at active phase; the ratio of cytokines in cell plasma of IFN-γ+IL-4, IFN-γ/TGF-β, and IFN-γ/IL-10, were also increased significantly (p<0.05). Conclusion: [circ1] In AA, the positive regulatory costimulatory increased while the negative regulatory costimulatory did not change or decreased, which shifted the immune balance to intensification. [circ2] Not only at priming stage but also at effective stage, the immune strengthened factors were higher than attenuated factors in AA.
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Yang, S. Y., S. Rhee, K. Welte, and B. Dupont. "Differential in vitro activation of CD8-CD4+ and CD4-CD8+ T lymphocytes by combinations of anti-CD2 and anti-CD3 antibodies." Journal of Immunology 140, no. 7 (April 1, 1988): 2115–20. http://dx.doi.org/10.4049/jimmunol.140.7.2115.
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Abstract Purified peripheral blood T lymphocytes and the CD8-CD4+ and CD4-CD8+ T cell subsets, exhaustively depleted of APC have been studied for their capacity to respond to mAb directed against the CD3-Ti Ag-specific TCR complex and against the CD2 SRBCR. It is demonstrated that high affinity IL-2R can be readily induced by either anti-CD3 and/or anti-CD2 stimulation. However, IL-2 production can be observed only in the CD4+CD8- T cell subset. These results clearly contrast data obtained with purified CD4-CD8+ T cells, which are able to proliferate when the CD3-Ti complex is activated in the presence of APC. The data presented in the present study demonstrate that a simplified model for T cell activation and clonal expansion of the two major T cell subsets involve only the CD3-Ti complex and the CD2 Ag. Under conditions where the activation signals for the T cells are restricted only to the activation of CD3-Ti and CD2, the CD4+CD8- T cells respond with IL-2 production and expression of high affinity IL-2R, whereas the CD4-CD8+ T cell subset depends on exogenous IL-2 provided by the CD4+CD8- cells. These data do not, however, exclude an involvement of other cell-surface signals for regulation and control of T cell activation and T cell effector functions.
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Blue, M. L., D. A. Hafler, K. A. Craig, H. Levine, and S. F. Schlossman. "Phosphorylation of CD4 and CD8 molecules following T cell triggering." Journal of Immunology 139, no. 12 (December 15, 1987): 3949–54. http://dx.doi.org/10.4049/jimmunol.139.12.3949.
Full textAbstract:
Abstract CD4 and CD8 molecules have been implicated in the regulation of T cell activation. In the present study, CD4 and CD8 were modified by increased phosphorylation when T cell clones or T cells were either exposed to phorbol-12-myristate- 13-acetate or were triggered via the CD3-T cell receptor complex. Activation of T cells through the CD2 sheep erythrocyte binding protein, using anti-T11(2) and -T11(3) antibodies, also resulted in CD4 and CD8 phosphorylation. These findings suggest that signals derived from two different receptor pathways can converge and result in similar molecular modifications of CD4 and CD8. Furthermore, phorbol myristate acetate treatment or activation via the CD2 pathway induced phosphorylation of the CD4 and CD8 molecules of thymocytes, suggesting that these molecules may be functional in thymus. Together, our findings indicate that CD4 and CD8 phosphorylation is a consequence of T cell triggering, and suggest that CD4 and CD8 phosphorylation may represent a molecular signaling mechanism among the CD3-T cell receptor complex, CD2, CD4, and CD8.
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Galy, A., S. Verma, A. Bárcena, and H. Spits. "Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development." Journal of Experimental Medicine 178, no. 2 (August 1, 1993): 391–401. http://dx.doi.org/10.1084/jem.178.2.391.
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Studies of the most immature T cell progenitors in the human thymus have been hampered by the lack of markers and assays that define these cells. In this report we used a novel human fetal thymic organ culture system to determine the potential of T cell precursors isolated from human postnatal thymus, to differentiate into CD3+ thymocytes, and to investigate early stages of human T cell development. It was found that thymocytes that lack the markers CD3, CD4, and CD8 (triple negative [TN]) can differentiate in an allogeneic organotypic thymic culture. The capacity of TN thymocytes to differentiate was exclusively confined to the CD34+ population. CD34- TN thymocytes failed to differentiate in this system. In contrast, cloned lines of CD3- thymocytes could only be established from CD34- TN thymocytes. Five subsets of CD3- thymocytes were found with the following phenotype: CD1-TN, CD1+TN, CD1+CD4+CD8-, CD1+CD4+CD8 alpha+ beta-, and CD1+CD4+CD8 alpha beta+. These subpopulations expressed decreasing levels of CD34. The CD1-CD3- population expressed the highest levels of CD34 supporting the notion that this population is the most immature T cell precursor in the thymus, whereas the CD1+CD4+CD8 alpha+ beta+ which did not express CD34 seems to be the most mature of these CD3- populations. This notion is supported by the observations that CD34+ cells isolated from fetal liver, which differentiated into T cells in a FTOC, developed into CD3+ cells via CD1- and CD4+CD8- intermediates. Based on these data, we present a model of early stages in human intrathymic development.
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Hirano, Naoto, Marcus O. Butler, and Lee M. Nadler. "4-1BB (CD137) or CD40 Signaling Fails To Improve the Expansion of Antigen Specific T Cells Demonstrated with Engagement of TCR, CD28 and CD83 Ligand." Blood 104, no. 11 (November 16, 2004): 2665. http://dx.doi.org/10.1182/blood.v104.11.2665.2665.
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Abstract Following the engagement of the T cell receptor by HLA class I and antigenic peptide, naïve CD8+ T cells are primed to receive one or more costimulatory signals. Some of these signals, which are upregulated on and delivered by mature dendritic cells, include members of the immunoglobulin superfamily such as CD80 and CD83. Using a K562 derived artificial antigen presenting cell (aAPC) that expresses HLA-A2, CD80, and CD83, we have shown that the coengagement of CD83 ligand:CD83 and CD28:CD80 induces prolonged and preferential expansion of antigen specific CD8+ T cells. Furthermore, we have found that CD28:CD80 signaling is required for the induction of CD83 ligand expression on peripheral T cells. In order to identify additional immunoaccessory molecules that can augment this response, we have developed a system to efficiently transfer any chosen molecule into aAPC. This provides an excellent platform for studying a potentially immunogenic molecule given the relative lack of immunoaccessory molecules expressed by K562 (i.e. no expression of CD40, CD40 ligand, CD83, CD86, 4-1BB, 4-1BB ligand, OX40, OX40 ligand, HLA class I, or HLA class II). Following the transduction of a candidate molecule under study, the stimulatory capacity of a supertransduced aAPC can be compared to parental aAPC. Attractive candidates include members of the TNF superfamily since they have been shown to deliver important costimulatory signals to T cells. It has been suggested that 4-1BB signaling supports the survival of newly generated effector CD8+ T cells and that CD40 signaling confers “CD4+ T cell-like” help directly to CD8+ T cells. However, the impact of each of these molecules on the stimulation and expansion of antigen specific T cells has not been exhaustively studied. In this report, we transfected aAPC with either 4-1BB ligand or CD40 ligand, allowing us to compare the stimulatory capacity of aAPC/CD40 ligand, aAPC/4-1BB ligand and parental aAPC. We stimulated HLA-A2 positive CD8+ T cells from healthy donors three times at weekly intervals with A2-restricted MART1 peptide pulsed onto either irradiated aAPC/CD40 ligand, aAPC/4-1BB ligand or parental aAPC. Between the stimulations, cells were treated with IL2 and IL15 every three days. When MART1 peptide pulsed aAPC/CD40 ligand were used as stimulators, the total number of CD8+ T cells and number of MART1 specific CD8+ T cells was slightly smaller. IFN-γ ELISPOT analysis revealed that functional avidity of T cell receptors on MART1 specific CD8+ T cells was similar whether they were stimulated by aAPC/CD40 ligand or parental aAPC. These results indicate that CD40 ligand, at least in the human setting, does not directly provide “CD4+ T cell-like” help to antigen-specific CD8+ T cells. In contrast, stimulation with peptide pulsed aAPC/4-1BB ligand did generate a larger total number of CD8+ T cells. Surprisingly, however, most of these T cells were not antigen specific. In fact, significantly fewer MART1 specific CD8+ T cells were generated by aAPC/4-1BB ligand compared to aAPC alone. These results suggest that, unlike CD80 and CD83, 4-1BB ligand delivers a costimulatory signal resulting in the non-specific expansion of CD8+ T cells. This work demonstrates the versatility of our system to dissect the function of particular immunoaccessory molecules and determine the optimal conditions in the stimulation and expansion of antigen-specific human CD8+ T cells ex vivo.
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Araujo, Maria das Graças Pereira, Victor lima Soares, Alessandra Suelen Jardim Silva, Gustavo Henrique de Medeiros Oliveira, Lenilton Silva DA Silva Júnior, Hugo Henrique de Freitas Ferreira, Rodrigo Villar Freitas, et al. "Importance of Flow Cytometry in the Diagnosis of Sezary Syndrome in the State of Rio Grande Do Norte, Brazil." Blood 136, Supplement 1 (November 5, 2020): 39–40. http://dx.doi.org/10.1182/blood-2020-143378.
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Introduction:Sézary Syndrome (SS) is a leukemic form of Fungal Mycosis (FM), a rare form of T-cell lymphoma, characterized by erythroderma, generalized lymphadenopathy and infiltration of neoplastic T cells (Sézary cells) with cerebriform nucleus on the skin, lymph nodes and peripheral blood, being observed predominantly in men and individuals over the age of 60 and black. In the diagnosis of SS / FM, at least one of the criteria must be observed: minimum absolute Sézary cells count of 1000/mm3, expansion of TCD4+ cells with a ratio CD4/CD8 >10, loss of at least one mature T cell antigens as CD2, CD3, CD5, CD7 and CD26 in associated with increased lymphocyte count with evidence of a clone of circulating TCD4 cells determined by flow cytometry (CF).Objective:To investigate MF/SS in patients diagnosed with cutaneous lymphoma by CF immunophenotyping. Methodology: Were investigated in samples of peripheral blood (SP) from 11 patients of both sexes with initial history of MF and confection of SS due to the presence of Sézary cells by cytomorphological analysis by CF constituted by a panel of conjugated monoclonal antibodies (AcMo) to fluorochromes and targeted to T lymphocytes: CD1a, CD2, CD3, CD5, CD7, subpopulation T-Helper (CD3+/CD4+) and T-cytotoxic (CD3+/CD8+), in addition to TCR a/b and TCR g/d; Natural Killer cells: CD16-56; B lymphocytes: CD19, CD20, CD21, CD22, CD23, IgM, IgG, IgD anti-kappa and anti-lambda, in addition to CD10, TdT, CD103, CD25, CD38 and CD138, CD45 and CD14. At the same time, a complete blood count with differential white blood cell count and investigation of clinical and demographic data such as age, sex and ethnicity/race were also performed. Results: Of the patients analyzed, 6/11 were male, the age group above 60 years and white individuals were also found in 6/11 patients. The blood count showed lymphocytosis in 9/11 patients with the presence of convoluted cells in all cases. The diagnosis of SS was confirmed by the presence of Sezary cells in PB counting above 1000/mm3, with an immunophenotype confirmed by the predominance of TCD4+ lymphocytes (CD4/CD8 ratio > 10.0), associated with the expression of CD5, CD2, TCR a/b, CD3 weakly expressed. CD7 was absent in 10/11 samples analyzed. Antigens related to B lymphocytes and NK cells were absent in neoplastic cells as well as CD10, TdT and CD1a.Conclusions:SS is a leukemic variant of FM, characterized by exfoliative erythroderma, associated with lymphadenopathy and leukemization of FM with the appearance of Sézary cells in PB. Because it is a rare and essential disease, an accurate diagnosis of these diseases is necessary, and FC is an important diagnostic confirmation tool for SS. Disclosures No relevant conflicts of interest to declare.
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Papadimitriou, T. I., A. van Caam, J. Lemmers, X. He, E. Vitters, M. Koenders, R. Smeets, et al. "AB0139 DEEP IMMUNE PHENOTYPING OF T LYMPHOCYTE SUBSETS IN SYSTEMIC SCLEROSIS PATHOPHYSIOLOGY AND FOLLOWING RESPONSE TO TARGETED CYTOTOXIC TREATMENT." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1199.1–1199. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3976.
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BackgroundAbnormalities in T lymphocyte populations are associated with the pathogenesis of many autoimmune diseases, such as systemic sclerosis (SSc). Various studies report on the aberrations of different T cell cytotoxic (CTL) and helper (Th) subsets that appear to be linked with inflammatory and/or fibrotic manifestations of patients with SSc. Since T cells seem to play a pivotal role in the pathophysiology of SSc, targeting the pathogenic T cell subsets might be a promising therapeutic option.ObjectivesHere we set out to comprehensively compare T lymphocyte phenotypes between SSc patients and healthy donors. We further test the in-vitro efficacy of a combination of anti-CD3/CD7 immunotoxins (CD3/CD7-IT), that have been developed to eliminate activated CD4+ and CD8+ T cells, to study specific sensitivity of T-cell subpopulations to CD3/CD7-IT.Methods30 SSc patients and 15 age and sex matched healthy donors were included. Of these patients, lymphocyte populations were quantified by 17-parameter flow cytometry of peripheral blood mononuclear cells (PBMCs) to identify CD4+ T helper cells (Th1, Th2, Th17, T peripheral helper), CD8+ naïve, memory, effector CTLs and senescent/exhausted subsets. We next developed a cell killing assay to evaluate the effect of T cell depletion. To address this, patients’ (N=6) PBMCs were first activated for 24 hours in the presence of phytohemagglutinin, followed by CD3/CD7-IT addition for 48 hours. Subset-specific T cell depletion was assessed by using a combination of CellTiter-Glow luminescent cell viability assay and multi-parameter flow cytometric (FCM) quantification of CD3/CD7-IT-induced cell death.ResultsFrequencies of effector CD8+ CTLs,Th2 and T peripheral helper cells were elevated in SSc patients compared to healthy controls. Furthermore, SSc patients exhibited lower percentages of the anti-fibrotic Th1 subset. A striking expansion of the senescent CD4+CD28- and CD8+CD28- populations was noted in patients, while these subsets were barely detectable in healthy controls. In-vitro adittion of anti-T cell immunotoxins effectively depleted 50 % of patients’ CD8+ T cells (including the CD8 effector subset) and 62% of CD4+ T cells (including Th2 and T peripheral helper cells). No difference in cytolytic sensitivity between different T cell subsets was observed.ConclusionOur findings demonstrate that deep FCM immunephenotyping reveals pathophysiological differences in peripheral T cell subsets of SSc patients. Strikingly, the developed cytolytic assays show that CD3/CD7-IT is able to target the potential disease-associated T cell subsets in an in-vitro setting.ReferencesNot applicableDisclosure of InterestsNone declared
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Zahran, Asmaa M., Khaled Saad, Khalid I. Elsayh, Abobakr Abdelmoghny, Mohamed Diab Aboul-Khair, Ali Sobhy, Yasser F. Abdel-Raheem, et al. "Myeloid-Derived Suppressor Cells and Costimulatory Molecules in Children With Allergic Rhinitis." Annals of Otology, Rhinology & Laryngology 128, no. 2 (November 18, 2018): 128–34. http://dx.doi.org/10.1177/0003489418812902.
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Objectives: The aim of this study is to assess the level of myeloid-derived suppressor cells (MDSCs) and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes in children with allergic rhinitis (AR). Methods: The study included 60 children with AR and 50 controls. Flow cytometry was performed to analyze MDSCs and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes. Results: The percentages of total and monocytic MDSCs and the expression of costimulatory molecule CD86 on monocytes were significantly higher in children with AR than in healthy controls. In addition, the expressions of CD28 on CD4+ and CD8+ were significantly elevated in AR patients. Conclusion: The present study demonstrated that the percentages of MDSCs were significantly elevated in AR children. Moreover, the expressions of CD28 on CD4+ and CD8+ were significantly higher in children with AR.
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Hori, T., and H. Spits. "Clonal analysis of human CD4-CD8-CD3- thymocytes highly purified from postnatal thymus." Journal of Immunology 146, no. 7 (April 1, 1991): 2116–21. http://dx.doi.org/10.4049/jimmunol.146.7.2116.
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Abstract Human triple-negative (CD4-CD8-CD3-) thymocytes purified from postnatal thymus by the use of magnetic bead columns and cell sorting were cultured in bulk or cloned with a feeder cell mixture of irradiated PBL, irradiated JY cells, and PHA. Triple-negative thymocytes proliferated well under these culture conditions, and after 12 days in bulk culture they remained triple negative. Limiting dilution experiments revealed that the frequency of clonogenic cells in fresh triple-negative thymocytes was less than 1%. Of 40 clones obtained in a representative experiment, 37 were triple negative and 3 were CD4+ TCR-alpha beta+. No TCR-gamma delta+ clones were isolated. Some of the triple-negative clones expressed CD16 and were apparently NK cells. Seven representative CD16-triple-negative clones were expanded and characterized in detail. These clones shared the common cell surface phenotype of CD1-CD2+CD3-CD4--CD8-CD5-CD7+CD16-CD56+. One of them expressed cytoplasmic CD3 delta and CD3 epsilon Ag, but these Ag were not detected in any peripheral blood-derived CD16- NK clones examined for comparison. The seven CD16- thymus-derived clones exhibited significant cytolytic activity against K562. The clone that expressed cytoplasmic CD3 Ag was shown to have the germ-line configuration of the TCR-beta and TCR-gamma genes. Thus, it is suggested that in vitro culture of triple-negative thymocytes can give rise to NK-like cells, including those that express cytoplasmic CD3 Ag. In contrast to previous reports, our results gave no evidence of differentiation of triple-negative thymocytes into TCR-alpha beta+ or TCR-gamma delta+ T cells.
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Greenberg, JM, and JH Kersey. "Terminal deoxynucleotidyl transferase expression can precede T cell receptor beta chain and gamma chain rearrangement in T cell acute lymphoblastic leukemia." Blood 69, no. 1 (January 1, 1987): 356–60. http://dx.doi.org/10.1182/blood.v69.1.356.356.
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Abstract The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) is thought to contribute to the diversity of certain immunoglobulin and T cell receptor gene rearrangements through the addition of random nucleotides at their variable (V)-joining (J) region junctions. An acute lymphoblastic leukemia (ALL) with an immature T cell phenotype (CD7+, CD5+, CD1+/-, CD2+/-, CD3-, CD4-, CD8-) was found to be TdT+ with germline immunoglobulin heavy chain, T cell receptor beta chain, and T cell gamma chain genes. The data indicate that TdT expression can precede T gamma and T beta rearrangement during T lymphoid ontogeny consistent with its proposed association with the T cell receptor rearrangement process. Southern analysis of certain cases of T-ALL may not result in the detection of a monoclonal population of cells.
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Greenberg, JM, and JH Kersey. "Terminal deoxynucleotidyl transferase expression can precede T cell receptor beta chain and gamma chain rearrangement in T cell acute lymphoblastic leukemia." Blood 69, no. 1 (January 1, 1987): 356–60. http://dx.doi.org/10.1182/blood.v69.1.356.bloodjournal691356.
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The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) is thought to contribute to the diversity of certain immunoglobulin and T cell receptor gene rearrangements through the addition of random nucleotides at their variable (V)-joining (J) region junctions. An acute lymphoblastic leukemia (ALL) with an immature T cell phenotype (CD7+, CD5+, CD1+/-, CD2+/-, CD3-, CD4-, CD8-) was found to be TdT+ with germline immunoglobulin heavy chain, T cell receptor beta chain, and T cell gamma chain genes. The data indicate that TdT expression can precede T gamma and T beta rearrangement during T lymphoid ontogeny consistent with its proposed association with the T cell receptor rearrangement process. Southern analysis of certain cases of T-ALL may not result in the detection of a monoclonal population of cells.
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Kay, NE, N. Bone, M. Hupke, and AP Dalmasso. "Expansion of a lymphocyte population co-expressing T4 (CD4) and T8 (CD8) antigens in the peripheral blood of a normal adult male." Blood 75, no. 10 (May 15, 1990): 2024–29. http://dx.doi.org/10.1182/blood.v75.10.2024.2024.
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Abstract Approximately 2% to 3% of circulating human T cells co-express CD4 and CD8 (CD4+, CD8+) T-cell antigens. These CD4+, CD8+ cells may be immature precursors that function to replenish functional T-cell subsets. We detected a very high level of CD4+, CD8+ cells in the peripheral blood lymphocytes of a healthy white male, ranging from 21% to 36%. The morphology of his peripheral blood lymphocytes was normal, and he has maintained an elevated level of CD4+, CD8+ cells without clinical disease over a 19-month observation period. The CD4+, CD8+ cells did not possess thymocyte membrane antigen (CD6), nor did they have increased Tac (CD25) antigen. His intact, purified blood T cells had a normal proliferative response to phytohemagglutinin and interleukin-2 (IL-2), provided help for B-cell proliferation at control levels and exposure to IL-2 resulted in generation of cytotoxic cells. However, the purified blood CD4+, CD8+ cells were deficient in these latter functions except for help in B-cell function. Despite defective function, the isolated CD4+, CD8+ cells co-expressed CD2 and CD3. Prolonged in vitro culture of CD4+, CD8+ cells was possible in the presence of recombinant IL-2. The cultured CD4+, CD8+ cells retained the double antigens (CD4 and CD8) throughout a 4-week period. It is likely these cells are less mature than CD4+, CD8- or CD4-, CD8+ T cells as the CD4+, CD8+ have less in vitro function than the former cells, but it is not yet clear if they mature into either CD4+, CD8-, or CD4-, CD8+ cells. Finally, the presence of an expanded, hypofunctioning CD4+, CD8+ cell population in a normal adult male is apparently compatible with excellent clinical health.
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Kay, NE, N. Bone, M. Hupke, and AP Dalmasso. "Expansion of a lymphocyte population co-expressing T4 (CD4) and T8 (CD8) antigens in the peripheral blood of a normal adult male." Blood 75, no. 10 (May 15, 1990): 2024–29. http://dx.doi.org/10.1182/blood.v75.10.2024.bloodjournal75102024.
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Approximately 2% to 3% of circulating human T cells co-express CD4 and CD8 (CD4+, CD8+) T-cell antigens. These CD4+, CD8+ cells may be immature precursors that function to replenish functional T-cell subsets. We detected a very high level of CD4+, CD8+ cells in the peripheral blood lymphocytes of a healthy white male, ranging from 21% to 36%. The morphology of his peripheral blood lymphocytes was normal, and he has maintained an elevated level of CD4+, CD8+ cells without clinical disease over a 19-month observation period. The CD4+, CD8+ cells did not possess thymocyte membrane antigen (CD6), nor did they have increased Tac (CD25) antigen. His intact, purified blood T cells had a normal proliferative response to phytohemagglutinin and interleukin-2 (IL-2), provided help for B-cell proliferation at control levels and exposure to IL-2 resulted in generation of cytotoxic cells. However, the purified blood CD4+, CD8+ cells were deficient in these latter functions except for help in B-cell function. Despite defective function, the isolated CD4+, CD8+ cells co-expressed CD2 and CD3. Prolonged in vitro culture of CD4+, CD8+ cells was possible in the presence of recombinant IL-2. The cultured CD4+, CD8+ cells retained the double antigens (CD4 and CD8) throughout a 4-week period. It is likely these cells are less mature than CD4+, CD8- or CD4-, CD8+ T cells as the CD4+, CD8+ have less in vitro function than the former cells, but it is not yet clear if they mature into either CD4+, CD8-, or CD4-, CD8+ cells. Finally, the presence of an expanded, hypofunctioning CD4+, CD8+ cell population in a normal adult male is apparently compatible with excellent clinical health.
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Bertho, JM, MD Mossalayi, AH Dalloul, G. Mouterde, and P. Debre. "Isolation of an early T-cell precursor (CFU-TL) from human bone marrow." Blood 75, no. 5 (March 1, 1990): 1064–68. http://dx.doi.org/10.1182/blood.v75.5.1064.1064.
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Abstract CD2-CD3-CD4-CD8- human bone marrow (BM) cells were previously shown to generate T-cell clones in vitro. This capacity was abolished after treatment of this population with anti-CD7 monoclonal antibody and complement. In this study, using rosetting with sheep erythrocytes, complement-dependent cytotoxicity, and specific immunoadherence method, we isolated a minor BM subset that contained more than 80% CD7+CD2-CD3- CD4-CD8- cells with small lymphoid cell morphology. They comprised most early T-cell precursors (CFU-TL) as they displayed high capacity to generate T-cell clones when cultured in limiting dilutions. CFU-TL nature of these cells was also confirmed by the sequential expression of mature T-cell specific markers on their surface after in vitro induction. This BM subset also contained 2% to 3% CFU-GM precursors. Together, these results pointed to the existence of BM CD7+CD2- precursors with high differentiation potential and showed the commitment of most of them to T-cell lineage.
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Bertho, JM, MD Mossalayi, AH Dalloul, G. Mouterde, and P. Debre. "Isolation of an early T-cell precursor (CFU-TL) from human bone marrow." Blood 75, no. 5 (March 1, 1990): 1064–68. http://dx.doi.org/10.1182/blood.v75.5.1064.bloodjournal7551064.
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CD2-CD3-CD4-CD8- human bone marrow (BM) cells were previously shown to generate T-cell clones in vitro. This capacity was abolished after treatment of this population with anti-CD7 monoclonal antibody and complement. In this study, using rosetting with sheep erythrocytes, complement-dependent cytotoxicity, and specific immunoadherence method, we isolated a minor BM subset that contained more than 80% CD7+CD2-CD3- CD4-CD8- cells with small lymphoid cell morphology. They comprised most early T-cell precursors (CFU-TL) as they displayed high capacity to generate T-cell clones when cultured in limiting dilutions. CFU-TL nature of these cells was also confirmed by the sequential expression of mature T-cell specific markers on their surface after in vitro induction. This BM subset also contained 2% to 3% CFU-GM precursors. Together, these results pointed to the existence of BM CD7+CD2- precursors with high differentiation potential and showed the commitment of most of them to T-cell lineage.
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Shaheen, M., L. Warmke, and M. Nassiri. "Focal Myositis with CD8+T-Cell predominance: an Inflammatory Myositis Mimicking a Soft Tissue Neoplasm." American Journal of Clinical Pathology 158, Supplement_1 (November 1, 2022): S109. http://dx.doi.org/10.1093/ajcp/aqac126.231.
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Abstract Introduction/Objective FM is a rare self-limiting T-cell rich lesion arising within muscles of young adults as a solitary lesion and can be confused with a variety of neoplastic/inflammatory conditions or lymphoma. Here we describe a rare T-cell rich variant of FM with CD8 predominance. Methods/Case Report A 51-year-old female presented with two-month history of left trapezius swelling. MRI showed an enhancing tumor within the muscle, suspicious of sarcoma, less likely myeloma. Results (if a Case Study enter NA) Biopsy showed diffuse infiltration of small lymphocytes in a fibrotic background and atrophic skeletal muscle. These lymphocytes stained positive for CD2, CD3, CD7, CD8, CD5 (partial), TIA1 (partial), CD43, CD57 and negative for CD4, CD30, CD56, CD57, granzyme B, perforin, BCL-6, BCL-2, Pax5, TCL1, and CD56. Ki-67 was (<10%) with few background CD20+ B cells. By flow cytometry, the CD8+ T-cells co-express CD2, CD3, CD7, with dim CD5 expression. TCR gene rearrangement study by PCR showed no clonal TCR Gamma gene rearrangement. Conclusion FM is extremely rare with only 22 cases well-described in the literature, all predominantly composed of CD4+ T-cells, clinically concerning for low-grade sarcomas, as inflammatory myofibroblastic tumor, inflammatory leiomyosarcoma, or liposarcoma. Careful analysis is essential for correct diagnosis. Mimics include other causes of myositis, such as polymyositis and inclusion body myositis. Depending on the extent of lymphocytic infiltrate, gene rearrangement studies might be necessary to rule out clonality. Recognition of this rare entity with excellent prognosis is crucial to provide appropriate management and avoid unnecessary, aggressive procedures.
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Yang, S. Y., S. M. Denning, S. Mizuno, B. Dupont, and B. F. Haynes. "A novel activation pathway for mature thymocytes. Costimulation of CD2 (T,p50) and CD28 (T,p44) induces autocrine interleukin 2/interleukin 2 receptor-mediated cell proliferation." Journal of Experimental Medicine 168, no. 4 (October 1, 1988): 1457–68. http://dx.doi.org/10.1084/jem.168.4.1457.
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Prior studies have shown that thymocytes, unlike peripheral T cells, do not proliferate in response to mitogenic combinations of anti-CD2 mAbs. The present study demonstrated that stimulation by a mitogenic anti-CD2 combination (9-1 plus 9.6) with anti-CD28 induced vigorous thymocyte proliferation in the absence of exogenous IL-2. This thymocyte proliferation was IL-2 dependent as shown by the complete inhibition using anti-IL-2-R mAbs. Induction of IL-2-R transcripts was detected in thymocytes stimulated by the anti-CD2 antibody combination alone or the anti-CD2 combination plus anti-CD28 antibody. However, induction of IL-2 transcripts was observed only in thymocytes triggered jointly by the anti-CD2 combination plus anti-CD28 antibodies. The double-negative (CD4-8-) or CD1+ thymocytes isolated by sorting or by panning were unresponsive to CD2/CD28 triggering. The same mitogenic signal could induce vigorous proliferation of thymocytes with a mature phenotype, i.e., CD3+CD4+ or CD3+CD8+ thymocytes. Immunofluorescence studies demonstrated that the majority of CD3+ thymocytes were CD28+, and most of the CD28+ cells were located in the medullary compartment of thymus. These results indicated that the T cell lineage surface molecules CD28 and CD2 are involved in the regulation of expansion and further differentiation of mature thymocytes.
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Kandilarova, Snezhina M., Atanaska I. Georgieva, Anastasiya P. Mihaylova, Marta P. Baleva, Valentina K. Atanasova, Diana V. Petrova, Georgi T. Popov, and Elissaveta J. Naumova. "Immune Cell Subsets Evaluation as a Predictive Tool for Hepatitis B Infection Outcome and Treatment Responsiveness." Folia Medica 59, no. 1 (March 1, 2017): 53–62. http://dx.doi.org/10.1515/folmed-2017-0008.
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AbstractBackground: The patient’s immune response is one of the major factors influencing HBV eradication or chronification, and it is thought to be responsible for the treatment success.Aim: Our study aimed to investigate whether cellular defense mechanisms are associated with the course of HBV infection (spontaneous recovery [SR] or chronification [CHB]) and with the therapeutic approach.Patients and methods: A total of 139 patients (118 with CHB, 21 SR) and 29 healthy individuals (HI) were immunophenotyped by flowcytometry. Fifty-six patients were treatment-naïve, 20 were treated with interferons and 42 with nucleoside/ nucleotide analogues.Results: Deficiency of T lymphocytes, helper-inducer (CD3+CD4+), suppressorcytotoxic (CD8+CD3+) and cytotoxic (CD8+CD11b-, CD8+CD28+) subsets, activated T cells (CD3+HLA-DR+, CD8+CD38+) and increased CD57+CD8- cells, elevated percentages of B lymphocytes and NKT cells were observed in CHB patients compared with HI. In SR patients, elevated CD8+CD11b+, NKT and activated T cells were found in comparison with controls. The higher values of T cells and their subsets in SR patients than in CHB patients reflect a recovery of cellular immunity in resolved HBV infection individuals. In both groups of treated patients, reduced T lymphocytes, CD3+CD4+ and CD8+CD38+ subsets were found in comparison with HI. Higher proportions of cytotoxic subsets were observed in treated patients compared with treatment-naïve CHB patients, more pronounced in the group with interferon therapy.Conclusion: Our data demonstrate that cellular immune profiles may be of prognostic value in predicting the clinical course of HBV infection, and the determination of the therapeutic response.
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Butler, Marcus O., Osamu Imataki, Yoshihiro Yamashita, Makito Tanaka, Sascha Ansén, Alla Berezovskaya, Matthew I. Milstein, et al. "Human CD4+ T Cells Help CD8+ T Cells Proliferate Ex Vivo by Secreting Both IL-2/IL-21 and Upregulating IL-21R." Blood 116, no. 21 (November 19, 2010): 4284. http://dx.doi.org/10.1182/blood.v116.21.4284.4284.
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Abstract Abstract 4284 While adoptive T cell therapy is a promising treatment modality for cancer, the optimal approach to generate T cell grafts ex vivo is currently unknown. CD4+ T cells help generate effective immune responses by sustaining CD8+ T cell proliferation, preventing exhaustion, and establishing long-lived functional memory. Incorporation of CD4+ T cell help to expand CD8+ T cells may provide a novel strategy to generate CTL grafts for adoptive therapy. In mouse models, common γ-chain receptor cytokines and CD40/CD40L can mediate CD4+ T cell help. However, CD4+ T cell help in humans has yet to be fully defined. We therefore developed an in vitro model for human CD4+ T cell help, which utilizes a novel artificial APC, aAPC/mOKT3. K562-based aAPC/mOKT3 expresses a membranous form of anti-CD3 mAb, CD54, CD58, CD80, and CD83 and stimulates CD3+ T cells regardless of HLA haplotype or antigen specificity. Using aAPC/mOKT3, we stimulated CD8+ T cells in the presence or absence of CD4+ T cells and found that CD8+ T cells expanded better when coincubated with CD4+ T cells, suggesting the presence of CD4+ T cell help. Coculture experiments using transwell plates suggested that the observed CD4+ T cell help of CD8+ T cell expansion involved both soluble factors and cell-cell contact. To identify molecules mediating the observed CD4+ T cell help, supernatants of CD4+/CD8+ T cell mixed and separate cultures were measured for a panel of soluble factors. IL-2 and IL-21 were detected at lower levels in mixed cultures, consistent with more consumption or less production of these cytokines. Blockade of either IL-2 or IL-21 in CD4+/CD8+ T cell mixed cultures resulted in a reduction of CD8+ T cell expansion, indicating that, for both cytokines, more consumption rather than less production occurred and that IL-2 and IL-21 may serve as mediators of CD4+ T cell help. However, the addition of IL-21 to CD8+ T cells stimulated with aAPC/mOKT3 in the presence of IL-2 did not improve CD8+ T cell expansion, suggesting that IL-2 plus IL-21 cannot solely replace CD4+ T cell help. We found that the presence of CD4+ T cells upregulated the expression of IL-21R on CD8+ T cells. When we introduced IL-21R on CD8+ T cells and stimulated with aAPC/mOKT3 in the presence of IL-2 and IL-21, CD8+ T cell proliferation was restored. These results suggest that CD4+ T cells help CD8+ T cells proliferate ex vivo by secreting both IL-2/IL-21 and upregulating IL-21R. When peripheral CD3+ T cells from normal donors were stimulated with aAPC/mOKT3, the number of both CD4+ and CD8+ T cells increased. However, in contrast to other pan T cell expansion systems, aAPC/mOKT3 preferentially expanded CD8+ T cells. No obvious skewing in the Vβ usage of both CD4+ and CD8+ T cell populations was revealed by TCR Vβ repertoire analysis, supporting “unbiased” T cell expansion by aAPC/mOKT3. Moreover, HLA-restricted antigen-specific CD8+ CTL with high functional avidity could be generated from CD3+ T cells initially expanded for 4 weeks using aAPC/mOKT3. Using aAPC/mOKT3, tumor-infiltrating lymphocytes (TIL) were successfully expanded without adding soluble mAb or allogeneic feeder cells. As in peripheral T cell cultures, CD8+ T cells predominantly expanded in all cultures, including those that initially contained a minimal percentage of CD8+ T cells. Importantly, Foxp3+ Treg cells did not proliferate. Expanded T cells highly expressed CD27 and CD28, which are associated with T cell survival and persistence in vivo. They also secreted high levels of IFN-γ and IL-2, lower amounts of IL-4, and no IL-10. These results demonstrate that the aAPC/mOKT3-based system can expand functional CD8+ TIL in the presence of autologous CD4+ T cells. In conclusion, we have determined that CD4+ T cell-dependent CD8+ T cell expansion required both soluble factors secreted by and cell contact with CD4+ T cells. Among the soluble factors secreted by CD4+ T cells, IL-2 and IL-21 were necessary. Furthermore, upregulation of IL-21R on CD8+ T cells by CD4+ T cells was critical for an optimized response to IL-21. Thus, in humans, CD4+ T cells help CD8+ T cells proliferate by secreting IL-2/IL-21 and upregulating IL-21R. Our aAPC enabled expansion of CD8+ TIL in the presence of CD4+ T cell help without using soluble mAb or allogeneic feeder cells. Taken together, these results demonstrate the indispensable role of CD4+ T cell help on expanding CD8+ T cells and suggest a novel strategy to generate anti-tumor T cells ex vivo for adoptive therapy. Disclosures: No relevant conflicts of interest to declare.
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Koide, J., and E. G. Engleman. "Differences in surface phenotype and mechanism of action between alloantigen-specific CD8+ cytotoxic and suppressor T cell clones." Journal of Immunology 144, no. 1 (January 1, 1990): 32–40. http://dx.doi.org/10.4049/jimmunol.144.1.32.
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Abstract We have previously demonstrated that fresh CD8+ T cells proliferate in response to autologous, alloantigen-primed CD4+ T cells, and differentiate into Ts cells, which inhibit the response of fresh T cells to the primary allogeneic stimulator cell but not irrelevant stimulators. Although such Ts do not have discernible cytolytic activity, like classical cytotoxic T cells (Tc) they express CD3 and CD8 on their surface and function in a class I MHC-restricted manner. Our study was an attempt to compare the surface phenotype and mechanism of action of Ts and Tc clones derived from the same individual. Ts clones were generated from donor JK by repeated stimulation of CD8+ T cells with an autologous CD4+ T inducer line specific for an allogeneic lymphoblastoid cell line (LCL). These clones were noncytolytic for either the inducer line or the allogeneic stimulator LCL. Tc clones, generated by direct stimulation of JK CD8+ T cells with the same allogeneic LCL, mediated potent, alloantigen-specific cytolysis. All Tc clones were alpha, beta TCR+, CD3+, CD4-, CD8+, CD11b-, and CD28+. Ts clones were also alpha, beta TCR+, CD3+, and CD8+, but in contrast to Tc clones, Ts clones were CD11b+ and CD28-. When added to MLR both Ts and Tc clones inhibited the response of fresh JK CD4+ T cells to the original but not irrelevant allogeneic LCL. However, Ts inhibited the response of only those CD4+ T cells that shared class I)MHC determinants with the Ts donor, whereas Tc inhibited the response of CD4+ T cells from all responders, regardless of HLA type. Pretreatment of Ts clones with mAb to CD2, CD3, or CD8 blocked suppression, whereas similar pretreatment of Tc clones blocked cytotoxicity in 4-h 51Cr release assays but had no effect on Tc-mediated suppression of the MLR. These results suggest that both Ts and Tc clones can inhibit the MLR but they do so through different mechanisms. Moreover, the maintenance of distinct surface phenotypes on these long term clones suggests that Ts may be a distinct sublineage of CD8+ T cells rather than a variant of CD8+ Tc.
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Reddy, A. C., and K. S. Reddy. "Pediatric Patient With Neurological And Leukemic Peripheral Blood Involvement By Small Cell Variant Of ALK- Positive Anaplastic Large Cell Lymphoma (ALCL): Case Study." American Journal of Clinical Pathology 154, Supplement_1 (October 2020): S113—S114. http://dx.doi.org/10.1093/ajcp/aqaa161.248.
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Abstract Casestudy Anaplastic large cell lymphoma (ALCL), is a T-cell lymphoma typically consisting of large lymphoid cells including characteristic horseshoe- shaped hallmark cells. The rare small cell morphological variant of ALCL may pose a challenge in diagnosis, especially when the initial presentation is unusual. Results Our patient, a 7-year-old girl presented with a headache. A complete blood count showed leukocytosis and anemia. The smear was reported to have segmented neutrophils, reactive lymphocytes, and monocytes. A spinal tap was performed and flow analysis identified a minute aberrant T cell population (0.3% of total), positive for CD3, CD4, bright CD7; negative CD5, CD8 in the CSF sample. The peripheral blood sample was reviewed again; some small- medium atypical lymphocytes, with irregular nuclear contours and cytoplasmic azurophilic granules were noted. Flow immunophenotyping displayed an aberrant T cell population positive for CD45, CD2, CD3, bright CD7, CD4, CD13; negative CD30, TdT CD5, CD8, CD117, CD34; consistent with T cell lymphoma/leukemia. A cell block prepared from peripheral blood sample showed blood with numerous atypical cells with irregular nuclei positive for ALK, CD30, CD3, CD4, CD7; negative CD5 and CD8. A diagnosis of leukemic ALK(+) ALCL was rendered, though classic hallmark cells were difficult to see. A marrow biopsy showed interstitial and sinusoidal pattern of mainly small to medium-sized cells with irregular nuclei. Molecular study revealed ALK gene alteration showing characteristic NPM1-ALK fusion. The patient underwent a bone bone marrow transplantation but recently relapsed with a submandibular lymph hode biopsy showing the presence of many larger ALCL cells. Conclusion Correct clinical diagnosis of the small-cell variant of ALCL is often challenging as the scarce “hallmark cells” are scattered and difficult to recognize. While leukemic peripheral blood involvement is rare in ALCL, an association has been reported with small-cell variants, which may be a potential explanation for the poor prognosis and aggressive nature of small-cell variant ALCL. A meticulous examination of peripheral blood smears, comprehensive immunophenotypic studies, and early bone marrow and lymph node/tissue biopsy are needed to facilitate diagnosis.
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Laharwani, H., K. Perrizo, S. Jain, and J. Lam. "A Rare Case of Chronic Lymphoproliferative Disorder of NK Cells with an Unusual Expression of CD57." American Journal of Clinical Pathology 154, Supplement_1 (October 2020): S101. http://dx.doi.org/10.1093/ajcp/aqaa161.221.
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Abstract Introduction/Objective Natural Killer cells (NK-cells) malignancies are extremely rare and the two NK-cell disorders involving the peripheral blood and bone marrow include chronic lymphoproliferative disorder of NK-cells (CLPDNK) and aggressive NK-cell leukemia (ANKL). ANKL is EBV associated with a prevalence in Asian adults and a fulminant clinical course leading to death within 2 months. Methods A 76-year-old female with a history of iron deficiency anemia presented for evaluation of lymphocytosis (78 TH/mm) and negative EBV with extreme fatigue, weight loss, and worsening weakness from the past 8 months. Results The peripheral and bone marrow aspirate showed an increase in granular lymphocytes with bland nuclei and abundant pale-staining cytoplasm containing fine to coarse azurophilic granules with no evidence of nuclear atypia. Flow cytometry demonstrated an atypical lymphocytic cell population comprising >50% of total marrow and peripheral blood lymphocytes demonstrating loss of CD56 and diminished CD7 expression. The analysis showed atypical lymphocytes with the following immunophenotype: CD2, CD8 (the majority, at least 75%),CD7 (dim), CD38, CD11c (subset) with no expression of CD3, CD5, CD4, CD56, or CD11c. Flow cytometry is important as it helps in the phenotypic detection of aberrancy. A broad panel of immunohistochemical stains revealed scattered positivity for CD3, CD4, CD7, CD8, TIA-1, granzyme, perforin, and tryptase and negative for CD56 and CD57. Our top differential with a similar clinical course included T-cell large granular lymphocytic leukemia which is characterized by a clonal proliferation of mature cytotoxic T cells and also has an indolent course. They show CD3 positivity by flow cytometry along with co-expression of NK cell-associated markers (CD16 and CD57), and variable expression of other pan T cell markers such as CD2, CD5, CD7. It is found incidentally in patients having cytopenias with a persistent increase in circulating mature NK-cells. Of note, the PET scan revealed splenomegaly with no other significant findings.The patient was started on steroids and is currently doing well. Conclusion Thus, overall morphologic, immunophenotypic, and molecular results with negative expression of surface or cytoplasmic CD3 as well as the absence of TCR expression were most consistent with CLPD-NK with an unusual expression of CD57 expression detected in flow cytometry.
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Battiwalla, Minoo, Paul K. Wallace, Laurie A. Ford, and Maria R. Baer. "Clinical and Pathological Presentation of T-Cell Large Granular Lymphocyte Proliferations (T-LGL): A Single Institution Experience." Blood 104, no. 11 (November 16, 2004): 3865. http://dx.doi.org/10.1182/blood.v104.11.3865.3865.
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Abstract Proliferations of T-cell large granular lymphocytes (T-LGL) are a rare and heterogeneous disease entity characterized by a chronic course, cytopenias and circulating cytotoxic T lymphocytes. We present the results of a single institution retrospective review of the clinical presentation of T-LGL proliferations. A total of 23 patients evaluated for cytopenias were identified as having T-LGL by flow cytometry, ten male and thirteen female, with a median age of 67 years at diagnosis. Twelve patients had a prior malignancy (non-Hodgkins lymphoma=4, MDS/AML=4, breast cancer=2, squamous cell cancer (SCC) of the skin =2, lung SCC=1, vocal cord SCC=1, uterine cancer=1) and five patients had a history of autoimmune disease (rheumatoid arthritis=2, vasculitis=1, polyarthritis=1, Wegener’s granulomatosis=1), while seven patients had no previous history of autoimmune disease or malignancy. Four patients with prior malignancy had active disease and this led to death in three. Of the twelve patients informative for T-cell receptor gene rearrangements, clonal populations were found in eight. All patients who had cytopenias requiring treatment were initially treated with cyclosporine monotherapy, with the further addition of growth factors if necessary. Multiparameter flow cytometric analysis of blood or bone marrow aspirates revealed that patients with a prior history of systemic malignancy had the common immunophenotype of CD3+(h), CD8+(h), CD2+, CD5+, CD7(h), CD56(h), CD57+, CD38+, CD16−. In contrast, patients who did not have a prior history of malignancy were CD3+, CD8+, CD2+, CD5+, CD7+, CD56+/−, CD57+, CD38+/(h), CD16+/− (h=heterogeneous). Thus patients with a prior malignancy had more heterogeneous expression of the T-cell markers CD3, CD8 and CD7 and were less likely to express CD16. We conclude that prior malignancy is more common in patients with T-LGL proliferations than previously recognized, may be twice as frequent as autoimmune disease in association with T-LGL and may have a distinct immunophenotype. Our data suggest that malignant cells may induce proliferations of T-LGL.
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Gorczyca, Wojciech, and Henry Y. Dong. "Subset of T-Cell Prolymphocytic Leukemia Expresses CD117. Potential Target for Therapy." Blood 104, no. 11 (November 16, 2004): 4540. http://dx.doi.org/10.1182/blood.v104.11.4540.4540.
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Abstract Introduction Excluding non-hematopoietic lesions, CD117 (c-kit) is expressed by erythroid, megakaryocytic and myeloid precursors, mature mast cells, subset of plasma cell neoplasm and occasional precursor lymphoblastic tumors. C-kit plays important role in T-cell development around birth, but the expression of CD117 in mature T-cell lymphoproliferations is rare. We present flow cytometry phenotypic data of 28 cases of T-cell prolymphocytic leukemia (T-PLL). Material and methods Multiparameter 4-color FC analysis was performed on peripheral blood and/or bone marrow aspirate samples using the following antibodies: CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD13, CD14, CD16, CD19, CD20, CD25, CD33, CD34, CD38, CD45, CD56, CD64, CD79a, CD117, TCRab/γδ, TdT, and HLA-DR. Fresh bone marrow aspirates and/or peripheral blood films and cytospin preparations from FC samples were stained with Wright-Giemsa. Results T-PLL was diagnosed 28 cases. The ages ranged from 43 to 92 years. Normal expression of pan-T cell antigens (CD2, CD3, CD5, CD7) was present in 57%. Abnormal expression of one, two and three antigens was noted in 21%, 11% and 11%, respectively. 4 cases showed aberrant expression of CD117. Those cases were always CD8-positive (50% of T-PLL were CD4+). There were no pan-myeloid (CD13, CD33) and blastic (TdT, CD34) markers present. Molecular studies confirmed clonal rearrangement of TCR. Discussion T-PLL is rare mature T-cell neoplasm characterized by marked lymphocytosis of small to medium-sized cells with conspicuous nucleoli. The response to conventional chemotherapy in T-PLL, similarly to other mature T-cell lymphoproliferations (except ALK+ anaplastic large cell lymphoma) generally is poor. While the use of alemtuzumab (Campath-1H) has improved remissions, the disease remains incurable. Novel treatment approaches, tailored to individual patients, and based on pathologic, phenotypic and molecular features will be crucial to improve survival for the patients with this disease. Based on the flow cytometry analysis of 28 cases of T-PLL we identified 4 cases with co-expression of CD117 (14%). When present, it is restricted to CD8+ tumors. We speculate that the expression of CD117 (c-kit) in these patients apart from its diagnostic utility, may serve as a criterion for a combination therapy with Campath-1H and imatinib mesylate.
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Зыблева, С. В., and О. А. Сердюкова. "Peculiarities of the Immune Status of Patients with Atopic Dermatitis." Лабораторная диагностика. Восточная Европа, no. 4 (January 18, 2021): 413–19. http://dx.doi.org/10.34883/pi.2020.9.4.006.
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Цель. Выявление особенностей проявлений состояния иммунного статуса пациентов с атопическим дерматитом на основе комплексной оценки характеризующих его клинико-иммунологических показателей.Материалы и методы. Обследовано 155 пациентов с диагнозом «атопический дерматит», а также 64 здоровых добровольца, составивших группу сравнения.Оценены у них уровни лейкоцитов, эозинофилов, CD3+CD8+, CD19+, CD3+, CD3-CD16+CD56+, CD3+CD16+CD56+, CD3+CD4+, CD3+HLA-DR+, CD3+CD8+, HLADR+, CD3+CD4+HLADR+, CD3+CD38+, CD3+CD8+CD38+, CD3+CD4+CD38+, CD3+CD4+CD25+, CD3+CD4+CD25+highCD127+low, IgM, IgG, IgA,IgЕ, C3-компонент комплемента, C4-компонент комплемента.Результаты. У пациентов с атопическим дерматитом выявлено увеличение уровня Т-лимфоцитов преимущественно за счет субпопуляции Т-хелперов, рост CD3+-лимфоцитов, несущих маркеры ранней (CD38) и поздней (HLA-DR) активации. Обнаружено увеличение концентрации в сыворотке основных иммуноглобулинов M, G, E, С3- и С4-компонентов комплемента. Отмечено увеличение уровня активированных CD3+CD4+CD25+ (Т-хелперы активированные) и CD3+CD4+CD25+highCD127+low (Т-регуляторные) лимфоцитов. Выявлены более низкие (относительно группы сравнения) уровни общего количества лимфоцитов и субпопуляции натуральных киллеров.Выводы. Установлен многофакторный характер этиопатогенеза атопического дерматита со свойственными ему процессами сложного взаимодействия между иммунологическими и экзогенными компонентами организма. Механизмы нарушения иммунного гомеостаза у пациентов с атопическим дерматитом в фазе рецидива связаны с количественным и качественным изменениями иммунокомпетентных клеток, нарушениями их регуляторного и врожденного звеньев иммунитета. Purpose. Comprehensive assessment of clinical and immunological parameters in patients with atopic dermatitis.Materials and methods. We have examined 155 patients with atopic dermatitis. We have studied the levels of leukocytes, eosinophils, CD3+CD8+, CD19+, CD3+, CD3-CD16+CD56+, CD3+CD16+CD56+, CD3+CD4+, CD3+HLA-DR+, CD3+CD8+, HLADR+, CD3+CD4+HLADR+, CD3+CD38+, CD3+CD8+CD38+, CD3+CD4+CD38+, CD3+CD4+CD25+, CD3+CD4+CD25+highCD127+low, IgM, IgG, IgA, IgЕ, complementcomponent C3, complement component C4. The comparison group consisted of 64 healthy volunteers.Results. In patients with atopic dermatitis, the increase of the level of T-lymphocytes was revealed, mainly due to T-helpers subpopulation, the growth of CD3+ lymphocytes carrying markers of early (CD38) and late (HLA-DR) activation. We determined the increase of the concentration of the main classesofimmunoglobulins(IgM, IgG, IgE), complementcomponents C3 and C4 intheserum. Increase of the level of activated CD3+CD4+CD25+ (activated T-helpers) and CD3+CD4+CD25+highCD127+low (T-regulatory) lymphocytes was noted. The levels of the total number of lymphocytes and the natural killer subpopulation were found to be lower than in the comparison group.Conclusion. Thus, the etiopathogenesis of atopic dermatitis is multifactorial, and it is characterized by complex interactions between immunological and exogenous components. The mechanisms of failure of immune homeostasis in patients with atopic dermatitis in the relapse phase are associated with quantitative and qualitative changes in the immune-competent cells, disorders of their regulatory component and innate immunity component.
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Sergeeva, Ekaterina Yu, Vladimir A. Khorzhevskii, and Tatiana G. Ruksha. "Pagetoid reticulosis." Vestnik dermatologii i venerologii 97, no. 6 (December 24, 2021): 81–86. http://dx.doi.org/10.25208/vdv1239.
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Pagetoid reticulosis (PR) is a rare type of mycosis fungoides. Clinical symptoms of PR can mimic other skin diseases of papulosquamous, neoplastic, and infectious origin that hampers PR diagnostics. The main histopathologic feature of PR is dense intraepidermal infiltration by medium to large-size lymphocytes through the epidermis leading to pagetoid plaque formation. There are three common immunophenotypes of PR: CD4-positive T-helper phenotype (CD3+, CD4+, CD8); T-cytotoxic/suppressor (CD3+, CD4, CD8+); and double negative phenotype (CD3+, CD4, CD8). The clinical case of PR with rare immunophenotype (CD2+, CD3+, CD8+ lymphoid infiltrate) is presented. The careful analysis of the symptoms, pathomorphological and immunohistochemical data is necessary for accurate PR diagnostics.
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Anasetti, C., P. Tan, J. A. Hansen, and P. J. Martin. "Induction of specific nonresponsiveness in unprimed human T cells by anti-CD3 antibody and alloantigen." Journal of Experimental Medicine 172, no. 6 (December 1, 1990): 1691–700. http://dx.doi.org/10.1084/jem.172.6.1691.
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Fresh peripheral blood mononuclear cells exposed to alloantigen for 3-8 d in the presence of anti-CD3 antibodies showed no response after restimulation with cells from the original donor but remained capable of responding to third-party donors. Antigen-specific nonresponsiveness was induced by both nonmitogenic and mitogenic anti-CD3 antibodies but not by antibodies against CD2, CD4, CD5, CD8, CD18, or CD28. Nonresponsiveness induced by anti-CD3 antibody in mixed leukocyte culture was sustained for at least 34 d from initiation of the culture and 26 d after removal of the antibody. Anti-CD3 antibody also induced antigen-specific nonresponsiveness in cytotoxic T cell generation assays. Anti-CD3 antibody did not induce nonresponsiveness in previously primed cells. Nonresponsiveness induced by anti-CD3 did not appear to be associated with suppressor cell activation. Thus, co-stimulation of the T cell receptor-CD3 complex on unprimed T cells with a fluid phase anti-CD3 antibody and allogenic major histocompatibility complex antigens can induce either clonal anergy or clonal deletion. These results suggest novel approaches for achieving transplantation tolerance.
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Falchi, Lorenzo, Ya-Hui Lin, Lauren Melendez, Paola Ghione, Colette Owens, Paul A. Hamlin, Jennifer Kimberly Lue, et al. "Potent CD8+ T-Cell Proliferation and Effector Differentiation Following Subcutaneous (SC) Mosunetuzumab Administration in Patients with Untreated, High Tumor-Burden Follicular Lymphoma (FL)." Blood 142, Supplement 1 (November 28, 2023): 6116. http://dx.doi.org/10.1182/blood-2023-189638.
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Introduction: Bispecific antibodies (BsAb) have emerged as a potent therapeutic option for patients with B-cell non-Hodgkin lymphoma, including FL. These drugs leverage endogenous CD3+ T-cells to enable cytotoxic tumor cell killing. While their mode of action has been hypothesized in in vitro and animal models, the mechanisms by which these drugs promote both initial and long-term immune-dependent disease control remains unknown. We recently initiated a multicenter phase 2 trial of the CD20xCD3 BsAb mosunetuzumab (mosun) as first-line therapy for patients with high-burden FL (NCT05389293). As part of this study, we performed serial sampling of both blood and lymph node tissues in order to elucidate T-cell changes associated with response and outcome. Here we present the first analysis of peripheral blood immune profiling. Methods: Patients with untreated, high-burden stage 2-4 FL in need of treatment received SC mosun at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Peripheral blood samples were obtained on C1D1, C1D8, C1D15, C2D1, C3D1, C5D1, and end of treatment (EOT, 24w from C1D1). Peripheral blood mononuclear cells (PBMCs) and plasma were isolated and cryopreserved. Samples were later thawed in batches and processed as follows: CITE-Seq + single-cell TCR sequencing was performed on viable CD11b-/CD19-/CD56-/CD3+ T-cells using the 10x Genomics Single Cell Immune Profiling Platform. RNA was extracted from 1 x 10 6 viable PBMCs using TriZol, followed by phenol/chloroform-based extraction, followed by bulk TCR sequencing using an in-house platform developed by MSKCC's Integrated Genomics Operation. The remaining cells were stained with antibodies targeting CD45RA, CD8, CD45, CD45RO, CD38, CD27, CD28, CXCR3, LAG-3, CD3, CD4, HLA-DR, CXCR5, CCR6, CD56, CD11b, CD19, CD39, PD-1, OX40, Tim-3, CCR4, Granzyme B, T-bet, FoxP3, Ki-67, and CTLA-4 and analyzed using a Cytek Aurora Spectral Cytometer. Flow cytometry analysis was performed using OMIQ. Statistical analyses were performed using a paired t-test. Results: A total of 45 samples obtained from 8 patients were analyzed, including samples from C1D1 (8), C1D8 (6), C1D15 (3), C2D1 (7), C3D1 (8), C5D1 (6), and EOT (7). High dimensional clustering of spectral cytometry data using the FlowSOM algorithm revealed 9 clusters of CD8+ T-cells corresponding to known CD8+ T-cell subsets. Among these subsets, we observed two distinct temporal patterns of CD8+ T-cells within the blood. On C1D8 there was a profound drop in circulating effector CD8+ T-cells as well as terminally differentiated CD8+ Temra cells (Figure 1), with a corresponding enrichment of naïve CD8+ T-cells (Figure). We also observed significant proliferation of newly activated T-cells on C1D8, followed by expansion of CD8+ T-cells expressing several activation and exhaustion markers including PD-1, Tim-3, and CD39, peaking on C2D1 (Figure 2). CD4+ T-cell responses were more modest with a small early increase in CD28+OX40+PD-1+ CD4+ T-cells on C1D8 and a drop in circulating GzmB+OX40+ CD4+ T-cells on C1D15. Conclusion: SC mosun therapy for newly diagnosed FL was associated with a unique peripheral blood immune profile, with early mobilization of pre-differentiated CD8+ T-cell effector cells and subsequent activation and expansion of newly primed CD8+ T-cells. Further immune phenotyping, including scRNA-seq and TCR clonal dynamics in the peripheral blood over time, as well as TCR clonality of distinct CD8+ and CD4+ T-cell populations are currently being analyzed on these and additional samples, and will be presented in detail.