Journal articles on the topic 'The immune response of T lymphocyte cell'
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1
Sen, Pritha, William A. Charini, Ramu A. Subbramanian, Edwin R. Manuel, Marcelo J. Kuroda, Patrick A. Autissier, and Norman L. Letvin. "Clonal Focusing of Epitope-Specific CD8+ T Lymphocytes in Rhesus Monkeys following Vaccination and Simian-Human Immunodeficiency Virus Challenge." Journal of Virology 82, no. 2 (October 31, 2007): 805–16. http://dx.doi.org/10.1128/jvi.01038-07.
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ABSTRACT To afford the greatest possible immune protection, candidate human immunodeficiency virus (HIV) vaccines must generate diverse and long-lasting CD8+ T lymphocyte responses. In the present study, we evaluate T-cell receptor Vβ (variable region beta) gene usage and a CDR3 (complementarity-determining region 3) sequence to assess the clonality of epitope-specific CD8+ T lymphocytes generated in rhesus monkeys following vaccination and simian-human immunodeficiency virus (SHIV) challenge. We found that vaccine-elicited epitope-specific CD8+ T lymphocytes have a clonal diversity comparable to those cells generated in response to SHIV infection. Moreover, we show that the clonal diversity of vaccine-elicited CD8+ T-lymphocyte responses is dictated by the epitope sequence and is not affected by the mode of antigen delivery to the immune system. Clonal CD8+ T-lymphocyte populations persisted following boosting with different vectors, and these clonal cell populations could be detected for as long as 4 years after SHIV challenge. Finally, we show that the breadth of these epitope-specific T lymphocytes transiently focuses in response to intense SHIV replication. These observations demonstrate the importance of the initial immune response to SHIV, induced by vaccination or generated during primary infection, in determining the clonal diversity of cell-mediated immune responses and highlight the focusing of this clonal diversity in the setting of high viral loads. Circumventing this restricted CD8+ T-lymphocyte clonal diversity may present a significant challenge in the development of an effective HIV vaccine strategy.
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Li, Lijin, Sharon M. Dial, Monika Schmelz, Margaret A. Rennels, and Neil M. Ampel. "Cellular Immune Suppressor Activity Resides in Lymphocyte Cell Clusters Adjacent to Granulomata in Human Coccidioidomycosis." Infection and Immunity 73, no. 7 (July 2005): 3923–28. http://dx.doi.org/10.1128/iai.73.7.3923-3928.2005.
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ABSTRACT The in situ immunologic response in human coccidioidomycosis remains undefined. To explore this further, pulmonary necrotizing coccidioidal granulomata were examined using immunohistochemical staining for lymphocyte subsets and for the cytokines interleukin-10 (IL-10) and gamma interferon (IFN-γ). Discrete perigranulomatous lymphocytic clusters were seen in eight of nine tissues examined. In these tissues, T lymphocytes (CD3+) significantly outnumbered B lymphocytes (CD20+) in the mantle area of the granulomata (P = 0.028), whereas the clusters were composed of roughly equal numbers of T and B lymphocytes. While the number of cells in the mantle expressing IL-10 was similar to those in the perigranulomatous clusters, there were significantly more cells expressing IFN-γ in the mantle than in the clusters (P = 0.037). Confocal microscopy revealed that CD4+ T lymphocytes and B lymphocytes are associated with IL-10 production. CD4+CD25+ T lymphocytes were identified in the perigranulomatous clusters but were not associated with IL-10 production. This is the first report noting perigranulomatous lymphocyte clusters and IL-10 in association with human coccidioidal granulomata and suggests that down-regulation of the cellular immune response is occurring within coccidioidal granulomata.
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Baszler, Timothy V., Varda Shkap, Waithaka Mwangi, Christopher J. Davies, Bruce A. Mathison, Monica Mazuz, Dror Resnikov, et al. "Bovine Immune Response to Inoculation with Neospora caninum Surface Antigen SRS2 Lipopeptides Mimics Immune Response to Infection with Live Parasites." Clinical and Vaccine Immunology 15, no. 4 (February 27, 2008): 659–67. http://dx.doi.org/10.1128/cvi.00436-07.
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ABSTRACT Infection of cattle with Neospora caninum protozoa, the causative agent of bovine protozoal abortion, results in robust cellular and humoral immune responses, particularly CD4+ T-lymphocyte activation and gamma interferon (IFN-γ) secretion. In the present study, N. caninum SRS2 (NcSRS2) T-lymphocyte-epitope-bearing subunits were incorporated into DNA and peptide preparations to assess CD4+ cell proliferation and IFN-γ T-lymphocyte-secretion immune responses in cattle with predetermined major histocompatibility complex (MHC) genotypes. In order to optimize dendritic-cell processing, NcSRS2 DNA vaccine was delivered with granulocyte macrophage-colony-stimulating factor and Flt3 ligand adjuvant. The synthesized NcSRS2 peptides were coupled with a palmitic acid molecule (lipopeptide) and delivered with Freund's adjuvant. Cattle vaccinated with NcSRS2 DNA vaccine alone did not induce T-lymphocyte activation or IFN-γ secretion, whereas subsequent booster inoculation with NcSRS2-lipopeptides induced robust NcSRS2-specific immune responses. Compared to the response in control animals, NcSRS2-lipopeptide-immunized cattle had significantly increased NcSRS2-specific T-lymphocyte proliferation, numbers of IFN-γ-secreting peripheral blood mononuclear cells, and immunoglobulin G1 (IgG1) and IgG2a antibody levels. The findings show that N. caninum NcSRS2 subunits bearing T-lymphocyte epitopes induced cell-mediated immune responses similar to the protective immune responses previously described against live parasite infection, namely T-lymphocyte activation and IFN-γ secretion. The findings support the investigation of NcSRS2 immunogens for protection against N. caninum-induced fetal infection and abortion in cattle.
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Jung, Jae Wook, Ae Rin Lee, Jaesung Kim, Young Rim Kim, Jassy Mary S. Lazarte, Jung Suk Lee, Kim D. Thompson, Hyeongsu Kim, and Tae Sung Jung. "Elucidating the Functional Roles of Helper and Cytotoxic T Cells in the Cell-Mediated Immune Responses of Olive Flounder (Paralichthys olivaceus)." International Journal of Molecular Sciences 22, no. 2 (January 15, 2021): 847. http://dx.doi.org/10.3390/ijms22020847.
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In higher vertebrates, helper and cytotoxic T cells, referred to as CD4 and CD8 T lymphocytes, respectively, are mainly associated with adaptive immunity. The adaptive immune system in teleosts involves T cells equivalent to those found in mammals. We previously generated monoclonal antibodies (mAbs) against olive flounder (Paralichthys olivaceus) CD4 T cells, CD4-1 and CD4-2, and used these to describe the olive flounder’s CD4 Tcell response during a viral infection. In the present study, we successfully produced mAbs against CD8 T lymphocytes and their specificities were confirmed using immuno-blotting, immunofluorescence staining, flow cytometry analysis andreverse transcription polymerase chain reaction (RT-PCR). The results showed that these mAbs are specific for CD8 T lymphocytes. We also investigated variations in CD4 and CD8 T cells populations, and analyzed the expression of immune-related genes expressed by these cells in fish infected with nervous necrosis virus or immunized with thymus dependent and independent antigens. We found that both CD4 and CD8 T lymphocyte populations significantly increased in these fish and Th1-related genes were up-regulated compared to the control group. Collectively, these findings suggest that the CD4 and CD8 T lymphocytes in olive flounder are similar to the helper and cytotoxic T cells found in mammals, and Th1 and cytotoxic immune responses are primarily involved in the early adaptive immune response against extracellular antigens.
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Parkman, Robertson, Geoff Cohen, Shelley L. Carter, Kenneth I. Weinberg, Bernadette Masinsin, Eva C. Guinan, Joanne Kurtzberg, John E. Wagner, and Nancy A. Kernan. "Antigen-Specific T Lymphocyte Function Following Unrelated Cord Blood Transplantation (UCBT)." Blood 106, no. 11 (November 16, 2005): 3032. http://dx.doi.org/10.1182/blood.v106.11.3032.3032.
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Abstract The T lymphocytes contained in cord blood are naïve and do not have antigen-specific function. Since the antigen-specific T lymphocytes contained in other hematopoietic stem cell (HSC) source may contribute to protective cellular immunity following transplantation, it has been hypothesized that the recipients of cord blood transplantation (CBT) might be at increased risk of opportunistic infections. The development of antigen-specific T lymphocyte function was measured in 153 recipients of unrelated cord blood transplants (UCBT) by determining antigen-specific T lymphocyte proliferation to the herpes viruses (CMV, HSC, VZV) for 3 years following UCBT. The first antigen-specific response was detected 29 days following transplantation to HSV. Positive T lymphocyte proliferative responses were detected in 66 recipients: 40 to VZV, 36 to HSV and 22 to CMV. Recipients with and without documented herpes infection/reactivation were equally likely to develop positive proliferative responses. The development of antigen-specific T lymphocyte function following UCBT documents successful immune reconstitution since the antigen-specific T lymphocytes are derived from naïve T lymphocytes or HSC, but not donor-derived antigen-specific T lymphocytes. The assessment of antigen-specific function following CBT is a model for the evaluation of post-transplant immune reconstitution without the compounding influence of donor derived antigen-specific function.
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Arsenio, Janilyn, Boyko Kakaradov, Gene Yeo, and John Chang. "Specification of CD8+ T lymphocyte fates during adaptive immunity revealed by single cell gene expression analyses (P1448)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 117.24. http://dx.doi.org/10.4049/jimmunol.190.supp.117.24.
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Abstract Although it is well established that heterogeneity of lymphocyte fate is an essential feature of adaptive immune responses, how and when these divergent cellular fates are specified remains unknown. It has been previously shown that a T lymphocyte responding to a microbial infection can undergo asymmetric division to yield two daughter cells that are differentially fated from inception. Such a model suggests that the progeny arising from each of the two differentially fated daughter cells might exhibit distinct patterns of gene expression. Because strategies analyzing bulk cell populations cannot distinguish differences among individual cells, we applied high-throughput single cell gene expression profiling to interrogate single CD8+ T lymphocytes throughout the course of an immune response to a bacterial infection. We demonstrate that terminally differentiated effector cells and self-renewing memory cells exhibit unique gene expression profiles. Moreover, we are able to identify cells early during the immune response, beginning with the first cell division, that exhibit distinct gene expression patterns characteristic of effector or memory cells. Finally, we derive a network model that allows us to predict the sequential activation of genes that orchestrate each cellular fate, providing a comprehensive view of CD8+ T lymphocyte differentiation. Together, these results provide novel insights into the specification of lymphocyte fates during an immune response.
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Kasaian, M. T., and C. A. Biron. "Effects of cyclosporin A on IL-2 production and lymphocyte proliferation during infection of mice with lymphocytic choriomeningitis virus." Journal of Immunology 144, no. 1 (January 1, 1990): 299–306. http://dx.doi.org/10.4049/jimmunol.144.1.299.
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Abstract The immunosuppressive agent, cyclosporin A (CsA) blocks production of IL-2 by lymphocytes in vitro, and impairs immune responses in vivo. During infection of mice with lymphocytic choriomeningitis virus (LCMV), IL-2 is produced by spleen lymphocytes with a time course corresponding to that of T cell activation and proliferation, but distinct from NK cell activation and proliferation. To evaluate the requirement for IL-2 in supporting lymphocyte proliferation in vivo, and to investigate the mechanisms of CsA-induced immunosuppression, the effects of CsA on LCMV-elicited responses were examined. CsA had profound effects on lymphocyte expansion and CTL activation on day 7 postinfection, the peak of the T cell response to LCMV. Proliferation of both the CD4+ and CD8+ T cell subsets was affected. Inhibition of T cell expansion was accompanied by the inhibition of IL-2 production and IL-2 responsiveness. In situ hybridization revealed a 50% reduction in the percentage of cells transcribing IL-2, suggesting that CsA blocked IL-2 production at the level of gene transcription. Transcripts of the gene for the IL-2R p55 chain are also normally elevated during infection, and CsA treatment resulted in an 80% reduction in the percentage of cells transcribing this gene. A reduced responsiveness of freshly isolated cells to rIL-2 in vitro correlated with the reduction of IL-2 receptor gene transcription positive cells. In contrast to effects of the drug on T cells, the level of NK cell activation was not decreased as a result of CsA treatment. These observations suggest that the IL-2 produced by lymphocytes in vivo in response to virus infection is required to promote the T cell response to LCMV, but do not support a role for IL-2 in NK cell activation under the conditions examined. Furthermore, the data demonstrate the profound inhibition of lymphocyte proliferation induced by CsA treatment during an in vivo immune response.
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Manuel, Edwin R., William A. Charini, Pritha Sen, Fred W. Peyerl, Marcelo J. Kuroda, Jörn E. Schmitz, Patrick Autissier, Dennis A. Sheeter, Bruce E. Torbett, and Norman L. Letvin. "Contribution of T-Cell Receptor Repertoire Breadth to the Dominance of Epitope-Specific CD8+ T-Lymphocyte Responses." Journal of Virology 80, no. 24 (October 11, 2006): 12032–40. http://dx.doi.org/10.1128/jvi.01479-06.
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ABSTRACT Dominant epitope-specific CD8+ T-lymphocyte responses play a central role in controlling viral spread. We explored the basis for the development of this focused immune response in simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys through the use of two dominant (p11C and p199RY) and two subdominant (p68A and p56A) epitopes. Using real-time PCR to quantitate T-cell receptor (TCR) variable region beta (Vβ) family usage, we show that CD8+ T-lymphocyte populations specific for dominant epitopes are characterized by a diverse Vβ repertoire, whereas those specific for subdominant epitopes employ a dramatically more focused Vβ repertoire. We also demonstrate that dominant epitope-specific CD8+ T lymphocytes employ TCRs with multiple CDR3 lengths, whereas subdominant epitope-specific cells employ TCRs with a more restricted CDR3 length. Thus, the relative dominance of an epitope-specific CD8+ T-lymphocyte response reflects the clonal diversity of that response. These findings suggest that the limited clonal repertoire of subdominant epitope-specific CD8+ T-lymphocyte populations may limit the ability of these epitope-specific T-lymphocyte populations to expand and therefore limit the ability of these cell populations to contribute to the control of viral replication.
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Puntigam, Lisa K., Sandra S. Jeske, Marlies Götz, Jochen Greiner, Simon Laban, Marie-Nicole Theodoraki, Johannes Doescher, et al. "Immune Checkpoint Expression on Immune Cells of HNSCC Patients and Modulation by Chemo- and Immunotherapy." International Journal of Molecular Sciences 21, no. 15 (July 22, 2020): 5181. http://dx.doi.org/10.3390/ijms21155181.
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Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) were isolated from head and neck squamous cell carcinoma (HNSCC) patients (n = 23) and compared to healthy donors (n = 23). Immune checkpoint expression (programmed cell death ligand 1 (PD-1), tumor necrosis factor receptor (TNFR)-related (GITR), CD137, tumor necrosis factor receptor superfamily member 4 (TNFRSF4) (OX40), t-cell immunoglobulin and mucin-domain containing-3 (TIM3), B- and T-lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG3)) was determined on immune cells by flow cytometry. PD-L1 expression was detected on tumor tissue by immunohistochemistry. Immune cells were treated with immuno- and chemotherapeutics to investigate treatment-specific change in immune checkpoint expression, in vitro. Specific changes of immune checkpoint expression were identified on PBL and TIL of HNSCC patients compared to healthy donors. Various chemotherapeutics acted differently on the expression of immune checkpoints. Changes of checkpoint expression were significantly less pronounced on regulatory T cells compared to other lymphocyte populations. Nivolumab treatment significantly reduced the receptor PD-1 on all analyzed T cell populations, in vitro. The specific immune checkpoint expression patterns in HNSCC patients and the investigated effects of immunomodulatory agents may improve the development and efficacy of targeted immunotherapy.
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Meythaler, Mareike, Amanda Martinot, Zichun Wang, Sarah Pryputniewicz, Melissa Kasheta, Binhua Ling, Preston A. Marx, Shawn O'Neil, and Amitinder Kaur. "Differential CD4+ T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection." Journal of Virology 83, no. 2 (November 5, 2008): 572–83. http://dx.doi.org/10.1128/jvi.01715-08.
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ABSTRACT In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection.
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Cardone, Marco, Kyojiro N. Ikeda, Barbara Varano, Sandra Gessani, and Lucia Conti. "HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes." Journal of Virology 89, no. 9 (February 11, 2015): 4798–808. http://dx.doi.org/10.1128/jvi.03681-14.
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ABSTRACTThe interplay between dendritic cells (DC) and γδ T lymphocytes represents a network of paracrine and cell contact interactions important for an integrated immune response to pathogens. HIV-1 infection dramatically affects the number and functions of both cell populations, and DC/γδ T cell cross talk may represent a target of virus-induced immune escape. We investigated whether HIV-exposed DC could deliver aberrant signals to interacting γδ T cells. Here we report that the interaction of human γδ T lymphocytes with HIV-1-exposed autologous monocyte-derived DC, but not direct exposure to the virus, impairs lymphocyte expansion and gamma interferon (IFN-γ) production in response to phosphoantigens. This effect is independent of virus strain and occurred in 55% of the donors analyzed. The donor-dependent variation observed relies on the responsiveness of DC to HIV-1 and is strictly related to the capacity of the virus to suppress the maturation-induced expression of interleukin 12 (IL-12). In fact, γδ T cell response to phosphoantigens is almost completely recovered when this cytokine is exogenously added to the DC/lymphocyte cocultures. Interestingly, we show that γδ T lymphocytes are recruited by HIV-1-exposed DC through a CCR5-mediated mechanism and exert a CCL4-mediated control on virus dissemination within DC and susceptible CD4+T lymphocytes. These results demonstrate an association between HIV-induced DC dysfunction and alterations of γδ T cell responses. The aberrant cross talk between these two cell populations may contribute to the pathogenesis of HIV infection by further reducing the strength of antiviral immune response.IMPORTANCEThis study provides new evidence on the mechanisms exploited by HIV-1 to evade the host immune response. We report that HIV-1 impairs the cross talk between DC and γδ T lymphocytes, by reducing the capacity of DC to promote functional γδ T cell activation. Interestingly, the virus does notper seinterfere with γδ T cell activation, thus highlighting the key role of early DC–HIV-1 interaction in this phenomenon. Furthermore, the results obtained unravel the novel role of γδ T cells in controlling HIV-1 dissemination within the DC population as well as virus transfer to susceptible CD4+T lymphocytes. The interactions of DC with innate lymphocytes represent a major control mechanism for an integrated immune response to infection. Understanding how HIV-1 harnesses these pathways may provide important insights on the pathogenesis of disease and offer new opportunities for therapeutic interventions.
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Pattanapanyasat, Kovit, Charin Thepthai, Pornvaree Lamchiagdhase, Surada Lerdwana, Kalaya Tachavanich, Prayoon Thanomsuk, Wanchai Wanachiwanawin, Suthat Fucharoen, and Janice M. Darden. "Lymphocyte subsets and specific T-cell immune response in thalassemia." Cytometry 42, no. 1 (February 15, 2000): 11–17. http://dx.doi.org/10.1002/(sici)1097-0320(20000215)42:1<11::aid-cyto3>3.0.co;2-1.
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Caruntu, Ana, Liliana Moraru, Mihaela Surcel, Adriana Munteanu, Daniel Octavian Costache, Cristiana Tanase, Carolina Constantin, Cristian Scheau, Monica Neagu, and Constantin Caruntu. "Persistent Changes of Peripheral Blood Lymphocyte Subsets in Patients with Oral Squamous Cell Carcinoma." Healthcare 10, no. 2 (February 10, 2022): 342. http://dx.doi.org/10.3390/healthcare10020342.
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Background: Oral squamous cell carcinoma (OSCC) is a common cancer with high morbidity and mortality. Alterations of antitumor immune responses are involved in the development of this malignancy, and investigation of immune changes in the peripheral blood of OSCC patients has aroused the interest of researchers. Methods: In our study, we assessed the proportions of CD3+ total T lymphocytes, CD3+CD4+ helper T lymphocytes, CD3+CD8+ suppressor/cytotoxic T lymphocytes, CD3−CD19+ total B lymphocytes, and CD3−CD16+CD56+ NK cells in the peripheral blood of OSCC patients. Results: The data obtained both pre- and post-therapy showed a similar level of total CD3+ T lymphocytes in OSCC patients and control subjects, pinpointing the stability of this immune parameter. On the other hand, pre-therapeutic data showed a lower proportion of helper T lymphocytes (CD4+), a significantly higher level of cytotoxic/suppressive T lymphocytes (CD8+), and a much lower CD4+ T lymphocyte/CD8+ T lymphocyte ratio compared to control subjects. Conversely, evaluation of circulating NK (CD16+) cells showed a markedly higher pre-therapeutic level compared to the control group. Conclusions: Our results related to immune changes in the peripheral blood add new information to this complex universe of connections between immuno-inflammatory processes and carcinogenesis.
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Trad, Malika, Alexandrine Gautheron, Jennifer Fraszczak, Darya Alizadeh, Claire Larmonier, Collin J. LaCasse, Sara Centuori, et al. "T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/891236.
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T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T-cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme.
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Rahbar, Mahtab, Keykhosro Mardanpour, and Sourena Mardanpour. "CD8+ T-cell lymphocyte infiltration predict clinical outcomes Wilms’ tumor." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e22001-e22001. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e22001.
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e22001 Background: The abundance and location of CD8+ tumor-infiltrating lymphocytes demonstrate important facets of the anticancer immune response. CD8-expressing lymphocytes have been used in immunotherapy for multiple cancers. This study aims to determine the association between the abundance and localization of CD8+ tumor-infiltrating lymphocytes and clinical outcomes Wilms’ tumor. Methods: This retrospective study employed 42 pediatric patients diagnosed with Wilms’ tumor. CD8+ tumor-infiltrating lymphocyte counts were calculated based on the mean percentage of stroma occupied by CD8+ lymphocytes at the center and the invasive border of the tumor using immunohistochemistry. Results: CD8+ tumor-infiltrating lymphocyte counts were significantly higher in the center and the invasive border of the early-stage tumor samples. CD8+ tumor-infiltrating lymphocytes in the invasive border and tumor center positively correlated with tumor invasion, regional lymph node invasion, histological type, metastasis, and stage of the tumor. A high CD8+ tumor-infiltrating lymphocyte scores at the invasive margin of the tumor correlated with low tumor recurrence. Low CD8+ tumor-infiltrating lymphocyte scores in the two tumor regions correlated with poor prognosis and shorter disease-free survival. Conclusions: Overall, these findings show that patients with high CD8+ tumor-infiltrating lymphocytes are associated with better clinical outcomes. Therefore, measuring the abundance of CD8+ tumor-infiltrating lymphocytes may be useful in predicting response to cancer immunotherapies.
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Soares, M. V. D., M. K. Maini, P. C. L. Beverley, M. Salmon, and A. N. Akbar. "Regulation of apoptosis and replicative senescence in CD8+ T cells from patients with viral infections." Biochemical Society Transactions 28, no. 2 (February 1, 2000): 255–58. http://dx.doi.org/10.1042/bst0280255.
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Activated T lymphocytes are generated during an immune response. The induction of T lymphocyte proliferation is one way in which cell numbers can be controlled. However, once generated, the increased numbers of cells must be removed in order to re-establish cellular homoeostasis within the immune system. In this paper we describe how the numbers of activated T cells can be regulated by two distinct mechanisms, namely apoptosis and replicative senescence. In addition, we suggest that the regulation of cell clearance, as opposed to cell persistence, after an immune response is intimately involved in the generation of immune memory.
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Yin, Xiangyun, Shuting Chen, and Stephanie C. Eisenbarth. "Dendritic Cell Regulation of T Helper Cells." Annual Review of Immunology 39, no. 1 (April 26, 2021): 759–90. http://dx.doi.org/10.1146/annurev-immunol-101819-025146.
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As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.
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Mardanpour, Keykhosro, Mahtab Rahbar, Sourena Mardanpour, Nyousha Mardanpour, and Mansour Rezaei. "CD8+ T-cell lymphocytes infiltration predict clinical outcomes in Wilms’ tumor." Tumor Biology 42, no. 12 (December 2020): 101042832097597. http://dx.doi.org/10.1177/1010428320975976.
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The abundance and location of CD8+ tumor-infiltrating lymphocytes demonstrate important facets of the anticancer immune response. CD8-expressing lymphocytes have been used in immunotherapy for multiple cancers. This study aims to determine the association between the abundance and localization of CD8+ tumor-infiltrating lymphocytes and clinical outcomes of Wilms’ tumor. This retrospective study employed 42 pediatric patients diagnosed with Wilms’ tumor. CD8+ tumor-infiltrating lymphocyte counts were calculated based on the mean percentage of stroma occupied by CD8+ lymphocytes at the center and the invasive border of the tumor using immunohistochemistry. CD8+ tumor-infiltrating lymphocyte counts were significantly higher in the center and the invasive border of the early-stage tumor samples. CD8+ tumor-infiltrating lymphocytes in the invasive border and tumor center positively correlated with tumor invasion, regional lymph node invasion, histological type, metastasis, and stage of the tumor. A high CD8+ tumor-infiltrating lymphocyte scores at the invasive margin of the tumor correlated with low tumor recurrence. Low CD8+ tumor-infiltrating lymphocyte scores in the two tumor regions correlated with poor prognosis and shorter disease-free survival. Overall, these findings show that patients with high CD8+ tumor-infiltrating lymphocytes are associated with better clinical outcomes. Therefore, measuring the abundance of CD8+ tumor-infiltrating lymphocytes may be useful in predicting response to cancer immunotherapies.
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Moll, J., A. Schmidt, H. van der Putten, R. Plug, H. Ponta, P. Herrlich, and M. Zöller. "Accelerated immune response in transgenic mice expressing rat CD44v4-v7 on T cells." Journal of Immunology 156, no. 6 (March 15, 1996): 2085–94. http://dx.doi.org/10.4049/jimmunol.156.6.2085.
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Abstract Splice variants of the glycoprotein CD44 (CD44v) that confer metastatic behavior to noninvasively growing rat tumor cells are transiently expressed on lymphocytes during activation. A mAb directed against an epitope encoded by CD44 exon v6 blocks both metastasis formations and lymphocyte activation, implicating CD44v in normal immune function. To explore the nature of this function of CD44v, transgenic mice were generated that constitutively express rat CD44v4-v7 on thymocytes and peripheral T cells. The number of lymphocytes as well as the distribution of lymphocyte subpopulations were similar in nontransgenic and rat CD44v4-v7 transgenic mice. T cells of the transgenic mice, however, responded faster to activating stimuli, particularly during primary stimulations with T cell mitogens and T-dependent Ags in vivo and in vitro. This accelerated response depended on the expression of the transgene product, since a rat CD44v6-specific Ab reverted the response profiles of the transgenic mice to those of nontransgenic mice. Since the transgene gained in vivo and in vitro functional activity only upon antigenic stimulation, it is likely that CD44 variant isoforms are involved in the process of signal transduction during lymphocyte activation.
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Rajakariar, Ravindra, Toby Lawrence, Jonas Bystrom, Mark Hilliard, Paul Colville-Nash, Geoff Bellingan, Desmond Fitzgerald, Muhammad M. Yaqoob, and Derek W. Gilroy. "Novel biphasic role for lymphocytes revealed during resolving inflammation." Blood 111, no. 8 (April 15, 2008): 4184–92. http://dx.doi.org/10.1182/blood-2007-08-108936.
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Abstract Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution. This is a classic view, and despite subpopulations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1−/− mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D2. However, upon resolution, lymphocytes repopulate the cavity comprising B1, natural killer (NK), γ/δ T, CD4+/CD25+, and B2 cells. Repopulating lymphocytes are dispensable for resolution, as inflammation in RAG1−/− and wild-type mice resolve uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox−/− mice, not only is resolution delayed compared with wild-type, but there is a failure of lymphocyte re-appearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.
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Finkelman, F. D., J. Ohara, D. K. Goroff, J. Smith, N. Villacreses, J. J. Mond, and W. E. Paul. "Production of BSF-1 during an in vivo, T-dependent immune response." Journal of Immunology 137, no. 9 (November 1, 1986): 2878–85. http://dx.doi.org/10.4049/jimmunol.137.9.2878.
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Abstract BSF-1, a cytokine produced by some T lymphocyte tumors, has been shown to act with anti-Ig antibodies to stimulate B lymphocyte proliferation, to independently induce resting B lymphocytes to increase their expression of surface Ia antigen, and to induce some activated B lymphocytes to differentiate into IgG1- or IgE-secreting cells. To determine whether BSF-1 might be secreted by normal lymphoid cells in the course of a physiologic immune response, BALB/c mice were injected with an affinity-purified goat antibody to mouse IgD (GaM delta), which induces the generation of a large, polyclonal T-dependent IgG1 response; 4-hr culture supernatants of spleen cells from these mice were prepared, and these supernatants were assayed for BSF-1 activity by analyzing their ability to induce BALB/c nu/nu spleen cells to increase their expression of cell surface Ia in vitro. Culture supernatants of unfractionated spleen cells removed from mice 4 to 8 days after GaM delta antibody injection induced substantial increases in B lymphocyte surface Ia expression; these increases were blocked by a monoclonal anti-BSF-1 antibody. Culture supernatants of spleen cells from untreated BALB/c mice or from untreated or GaM delta antibody-treated BALB/c nu/nu mice induced small to moderate increases in B cell surface Ia expression, and GaM delta antibody itself induced large increases in B cell surface Ia expression; however, these increases were not significantly blocked by a monoclonal anti-BSF-1 antibody. A culture supernatant of T cell-enriched spleen cells from untreated mice induced small increases in B cell surface Ia expression that were inhibited by anti-BSF-1 antibody, as was the larger increase in B cell Ia expression induced by a culture supernatant of T cell-enriched spleen cells from mice sacrificed 3 days after GaM delta injection. On the other hand, T cell-depleted spleen cells from BALB/c mice injected with GaM delta antibody 7 days before sacrifice failed to generate culture supernatants with BSF-1 activity. Supernatants prepared from spleen cells taken from untreated mice or mice treated with GaM delta antibody 1 to 3 days before sacrifice did not block the ability of purified BSF-1 to induce an increase in B cell surface Ia expression, and thus did not contain inhibitors of BSF-1 activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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Dowd, Pauline S., J. Kelleher., and P. J. Guillou. "T-lymphocyte subsets and interleukin-2 production in zinc-deficient rats." British Journal of Nutrition 55, no. 1 (January 1986): 59–69. http://dx.doi.org/10.1079/bjn19860010.
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1. It has been suggested that zinc-deficiency impairs cellular (T-lymphocyte-mediated) immune responses via a selective effect on helper T-lymphocytes. We have addressed this question in the rat by employing recently developed reagents in the form of monoclonal antibodies which specifically identify rat T-lymphocyte subsets (identifying total T-cells, helper T-cells and suppressor T-cells) and also by quantifying helper T-cell function by measurement of the helper T-cell-derived molecule interleukin-2 (IL-2).2. Zn-deficiency induced T-cell atrophy (assessed morphologically and phenotypically with anti-rat T-cell monoclonal antibodies) in both peripheral blood and spleen. The use of these specific monoclonal antibodies failed to demonstrate a selective effect of Zn deficiency on the helper T-cell fraction of the total T-lymphocyte population.3. In contrast, the results of functional assays of the T-lymphocyte response were dependent on the conditions of culture but suggested that the generation of IL-2 and its corresponding receptor were determined by the intracellular Zn status. Thus, in vivo, helper T-lymphocyte numbers are non-specifically reduced since other T-cell subsets are also reduced in response to appropriate stimulation. The functional consequences of this are dependent on the intracellular concentration of Zn but appear to influence both IL-2 production and its receptors on activated T-cells.
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Grailer, Jamison J., Rochelle M. Conway, and Douglas A. Steeber. "Lymphocyte subset recruitment during an immune response differs between peripheral and mucosal lymphoid tissues (95.7)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 95.7. http://dx.doi.org/10.4049/jimmunol.182.supp.95.7.
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Abstract Lymphocyte recirculation through peripheral lymphoid tissue depends primarily on the adhesion molecules L-selectin and α4β7 integrin. While most naïve lymphocytes express both molecules, subset-specific differences exist. These differences, along with tissue-specific expression of vascular ligands, results in preferential migration patterns among subsets. In the present studies, lymphocyte subset migration into peripheral (PLN) and mesenteric lymph nodes (MLN) was examined following s.c. and oral immunization, respectively. Naïve CD4+ T cell migration into PLNs increased after s.c. immunization with KLH-alum, peaking at 72 h. Naïve CD8+ T cell migration started lower than CD4+ cells, but increased steadily following immunization, reaching equivalent levels after 7 days. By comparison, B cell migration increased little and plateaued after 24 h. Among memory/effector cells, CD8+ T cell migration increased gradually up to 5 days post-immunization, and decreased thereafter, while CD4+ T cells increased modestly and plateaued after 24 h. In contrast to activated PLNs, oral immunization with cholera toxin + KLH resulted in peak increases in migration of all T cell subsets into the MLN at 24 h post-immunization. Interestingly, no changes in migration into the Peyer's patches were observed. These results indicate that activated PLN and MLN have different recruitment kinetics for lymphocyte subsets.
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Asquith, Becca, Emmanuel Hanon, Graham P. Taylor, and Charles R. M. Bangham. "Is human T–cell lymphotropic virus type I really silent?" Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1400 (August 29, 2000): 1013–19. http://dx.doi.org/10.1098/rstb.2000.0638.
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The role of the cellular immune response to human T–cell lymphotropic virus type I (HTLV–I) is not fully understood. The low level of HTLV–I protein expression in peripheral blood lymphocytes has led to the widely held belief that HTLV–I is transcriptionally silent in vivo . However, most HTLV–I–infected individuals mount a strong and persistently activated cytotoxic T–lymphocyte (CTL) response to the virus; this observation implies that there is abundant chronic transcription of HTLV–I genes. Here we show that HTLV–I Tax protein expression rises quickly in freshly isolated peripheral blood lymphocytes, but that expressing cells are rapidly killed by CTLs. Mathematical analysis of these results indicates that the CTL response is extremely efficient and that the half–life of a Tax–expressing cell is less than a day. We propose that HTLV–I protein expression in circulating lymphocytes is undetectable by current techniques because of the efficiency of the CTL–mediated immune surveillance in vivo .
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Hickling, Julian K. "Measuring human T-lymphocyte function." Expert Reviews in Molecular Medicine 1, no. 6 (October 13, 1998): 1–20. http://dx.doi.org/10.1017/s1462399498000313.
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T lymphocytes (T cells) play critical roles in the regulation of immune responses, and are responsible for mediating many of the effector mechanisms of the immune system. For this reason, there has always been a need for assays to measure accurately the activity of populations of T cells, both in model (animal) systems and in humans. The expansion of the biotechnology industry has led to a dramatic increase in the number of novel immunotherapeutics that are being developed for the treatment of cancer, autoimmune disorders and infectious diseases. This increase in activity in the field of immunotherapy, coupled with the expense of clinical trials, has led to renewed interest in methods that accurately assess T-cell function, as researchers seek to maximise the amount of information that can be obtained from each clinical study. Assessing the quantitative and qualitative nature of a T-cell response, for example following vaccination or immunosuppressive therapy, can provide valuable information about the efficacy of a treatment, in place of a clinical endpoint. This article reviews some of the established methods that are used to monitor human T-cell activity, and describes some new approaches that are in development to increase the speed, sensitivity and relevance of such methods.
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Mohamed, Hager, Rachel Berman, Jennifer Connors, Elias K. Haddad, Vandana Miller, Michael R. Nonnemacher, Will Dampier, Brian Wigdahl, and Fred C. Krebs. "Immunomodulatory Effects of Non-Thermal Plasma in a Model for Latent HIV-1 Infection: Implications for an HIV-1-Specific Immunotherapy." Biomedicines 11, no. 1 (January 3, 2023): 122. http://dx.doi.org/10.3390/biomedicines11010122.
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In people living with HIV-1 (PLWH), antiretroviral therapy (ART) eventually becomes necessary to suppress the emergence of human immunodeficiency virus type 1 (HIV-1) replication from latent reservoirs because HIV-1-specific immune responses in PLWH are suboptimal. Immunotherapies that enhance anti-HIV-1 immune responses for better control of virus reemergence from latent reservoirs are postulated to offer ART-free control of HIV-1. Toward the goal of developing an HIV-1-specific immunotherapy based on non-thermal plasma (NTP), the early immunological responses to NTP-exposed latently infected T lymphocytes were examined. Application of NTP to the J-Lat T-lymphocyte cell line (clones 10.6 and 15.4) stimulated monocyte recruitment and macrophage maturation, which are key steps in initiation of an immune response. In contrast, CD8+ T lymphocytes in a mixed lymphocyte reaction assay were not stimulated by the presence of NTP-exposed J-Lat cells. Furthermore, co-culture of NTP-exposed J-Lat cells with mature phagocytes did not modulate their antigen presentation to primary CD8+ T lymphocytes (cross-presentation). However, reactivation from latency was stimulated in a clone-specific manner by NTP. Overall, these studies, which demonstrated that ex vivo application of NTP to latently infected lymphocytes can stimulate key immune cell responses, advance the development of an NTP-based immunotherapy that will provide ART-free control of HIV-1 reactivation in PLWH.
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Moussa Agha, Douâa, Redouane Rouas, Mehdi Najar, Fatima Bouhtit, Hussein Fayyad-Kazan, Laurence Lagneaux, Dominique Bron, Nathalie Meuleman, Philippe Lewalle, and Makram Merimi. "Impact of Bone Marrow miR-21 Expression on Acute Myeloid Leukemia T Lymphocyte Fragility and Dysfunction." Cells 9, no. 9 (September 8, 2020): 2053. http://dx.doi.org/10.3390/cells9092053.
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Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy in which antitumor immunity is impaired. The therapeutic management of AML requires understanding the mechanisms involved in the fragility and immune dysfunction of AML T lymphocytes. Methods: In this study, T lymphocytes from healthy donors (HD) and AML patients were used. Extracellular vesicles (EVs) from leukemic cells were screened for their microRNA content and impact on T lymphocytes. Flow cytometry, transcriptomic as well as lentiviral transduction techniques were used to carry out the research. Results: We observed increased cell death of T lymphocytes from AML patients. EVs from leukemia myeloid cell lines harbored several miRNAs, including miR-21, and were able to induce T lymphocyte death. Compared to that in HD, miR-21 was overexpressed in both the bone marrow fluid and infiltrating T lymphocytes of AML patients. MiR-21 induces T lymphocyte cell death by upregulating proapoptotic gene expression. It also increases the immunosuppressive profile of T lymphocytes by upregulating the IL13, IL4, IL10, and FoxP3 genes. Conclusions: Our results demonstrate that miR-21 plays a significant role in AML T lymphocyte dysfunction and apoptosis. Targeting miR-21 may be a novel approach to restore the efficacy of the immune response against AML.
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Lis, Magdalena, Marianna Szczypka, Agnieszka Suszko-Pawłowska, Anna Sokół-Łętowska, Alicja Kucharska, and Bożena Obmińska-Mrukowicz. "Hawthorn (Crataegus monogyna) Phenolic Extract Modulates Lymphocyte Subsets and Humoral Immune Response in Mice." Planta Medica 86, no. 02 (November 19, 2019): 160–68. http://dx.doi.org/10.1055/a-1045-5437.
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AbstractThis study investigated the effect of hawthorn (Crataegus monogyna) phenolic extract on lymphocyte subsets in the lymphoid organs in nonimmunized mice and on humoral immune response in sheep red blood cell-immunized mice. Hawthorn phenolic extract (50, 100, 200 mg/kg) was administered orally five or ten times. Sheep red blood cells were injected 24 h after administration of the last extract dose. The lymphocyte subsets were assessed 24 and 72 h after the last dose. Humoral immune response was determined 4 and 7 days after immunization. Five doses of the extract decreased the percentage of CD4−CD8− and CD4+ thymocytes but elevated the percentage of CD4+CD8+ and CD8+ thymic cells. The extract increased the total number, percentage, and absolute count of T and B splenocytes. When administered five times, it lowered the percentage of T lymphocytes, but boosted the population of B lymphocytes of mesenteric lymph nodes (after 24 h). However, a rise in the population of T lymphocytes was observed 72 h after five and ten doses. The extract administered ten times elevated the number of plaque-forming cells and total anti-sheep red blood cell hemagglutinin titer but reduced the 2-ME-resistant antibody titer (day 7). At the same time, five doses of the extract increased antibody titers. Considering its impact on lymphocyte subsets and humoral immune response, hawthorn extract may be used as an immunomodulator.
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Halme, S., J. Latvala, R. Karttunen, I. Palatsi, P. Saikku, and H. M. Surcel. "Cell-Mediated Immune Response during Primary Chlamydia pneumoniae Infection." Infection and Immunity 68, no. 12 (December 1, 2000): 7156–58. http://dx.doi.org/10.1128/iai.68.12.7156-7158.2000.
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ABSTRACT The development of Chlamydia pneumoniae-specific cell-mediated immunity was studied during a primary C. pneumoniae infection. The immune response was detected as positive lymphocyte proliferation and secretion of interferon gamma.C. pneumoniae-induced activation of both CD4+and CD8+ T cells was detected in the early phase of infection, but activation of only CD4+ T cells was detected in the later stage.
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Schirren, CA, H. Volpel, and SC Meuer. "Adhesion molecules on freshly recovered T leukemias promote tumor- directed lympholysis." Blood 79, no. 1 (January 1, 1992): 138–43. http://dx.doi.org/10.1182/blood.v79.1.138.138.
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Abstract Besides facilitating cell to cell adhesion, the molecular interactions between CD2 and its ligand CD58 (lymphocyte function-associated antigen- 3 [LFA-3]), as well as between CD11a/18 (LFA-1) and CD54 (intercellular adhesion molecule-1) have recently been recognized to participate in lymphocyte activation, recirculation, and effector function, including cytolytic activity towards tumor cells. We have investigated the role of CD2/CD58 and CD11a/18/CD54 interactions in cellular immune responses directed towards freshly recovered human T-cell leukemias. The data support the notion that downregulation of CD54 and CD58 correlates with enhanced numbers of blasts in circulation and unsusceptibility to killing by autologous cytotoxic lymphocytes. Importantly, after induction of CD54 and CD58 expression on leukemic cells by recombinant cytokines such as tumor necrosis factor-alpha, tumor cells become highly susceptible to lymphocyte-mediated lysis in vitro. Our findings, therefore, stress the point that successful immunotherapy of malignant disease may be facilitated by influencing not only the immune response itself, but also adhesion molecules on the malignant tumor targets.
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Schirren, CA, H. Volpel, and SC Meuer. "Adhesion molecules on freshly recovered T leukemias promote tumor- directed lympholysis." Blood 79, no. 1 (January 1, 1992): 138–43. http://dx.doi.org/10.1182/blood.v79.1.138.bloodjournal791138.
Full textAbstract:
Besides facilitating cell to cell adhesion, the molecular interactions between CD2 and its ligand CD58 (lymphocyte function-associated antigen- 3 [LFA-3]), as well as between CD11a/18 (LFA-1) and CD54 (intercellular adhesion molecule-1) have recently been recognized to participate in lymphocyte activation, recirculation, and effector function, including cytolytic activity towards tumor cells. We have investigated the role of CD2/CD58 and CD11a/18/CD54 interactions in cellular immune responses directed towards freshly recovered human T-cell leukemias. The data support the notion that downregulation of CD54 and CD58 correlates with enhanced numbers of blasts in circulation and unsusceptibility to killing by autologous cytotoxic lymphocytes. Importantly, after induction of CD54 and CD58 expression on leukemic cells by recombinant cytokines such as tumor necrosis factor-alpha, tumor cells become highly susceptible to lymphocyte-mediated lysis in vitro. Our findings, therefore, stress the point that successful immunotherapy of malignant disease may be facilitated by influencing not only the immune response itself, but also adhesion molecules on the malignant tumor targets.
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Ghaffari, Guity, Dominick J. Passalacqua, Bradley S. Bender, Debora J. Briggs, Maureen M. Goodenow, and John W. Sleasman. "Human Lymphocyte Proliferation Responses following Primary Immunization with Rabies Vaccine as Neoantigen." Clinical Diagnostic Laboratory Immunology 8, no. 5 (September 1, 2001): 880–83. http://dx.doi.org/10.1128/cdli.8.5.880-883.2001.
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ABSTRACT Evaluation of the T-cell immune response following primary antigenic challenge with a neoantigen is a critical aspect of assessment of the cellular immune response. While many antigens can be used to accurately assess in vitro T-cell proliferation to a recall antigen, only a few neoantigens have been tested for their capacities to measure T-cell responses in vitro to a primary immunization. Rabies vaccination is an excellent candidate for the testing of T-cell proliferation responses to a primary immunization because few individuals have been exposed to rabies virus antigens. In the present study 14 rabies vaccine-naı̈ve, healthy adult volunteers were immunized against rabies virus, and T-cell proliferation and antibody responses were measured before and after vaccination. Optimal lymphocyte proliferation to soluble rabies virus antigen occurred after 8 days in culture. The average level of uptake of tritiated thymidine postimmunization was 29,620 ± 4,448 cpm, whereas preimmunization levels were 12,660 ± 3,448 cpm (P = 0.002). All individuals showed increases in rabies virus antibody titers from <0.05 to 5.59 ± 1.64 IU/ml. The degree of proliferation to tetanus toxoid as a recall antigen was similar to the response to rabies virus antigen among the cohort. Due to high levels of preimmunization proliferation, four subjects failed to demonstrate a twofold increase in response to rabies virus antigen. The high levels of T-cell responses may be due to a viral superantigen effect in some individuals. Rabies vaccination offers a safe and effective means for measurement of both T- and B-cell immune responses to a neoantigen in healthy and immune suppressed individuals.
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Montelli, Terezinha C. B., Angela M. V. C. Soares, Maria R. Parise-Fortes, Maria T. Rezkallah-Iwasso, Niura M. R. Padula, and Maria Terezinha S. Peraçoli. "Alterations of cell-mediated immune response in children with febrile seizures." Arquivos de Neuro-Psiquiatria 55, no. 2 (June 1997): 193–98. http://dx.doi.org/10.1590/s0004-282x1997000200005.
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The aim of the present investigation was to study the distribution of T-cell subsets in peripheral blood defined by monoclonal antibodies and by the lymphocyte proliferative response to phytohemagglutinin (PH A) in 30 children with febrile seizures and in 14 age-matched control subjects. Frequent respiratory, urinary and dermatologic infections were observed in 22 patients. The immunologic parameters showed that 64% of the patients presented an increased number of CD8+ cells and a low helper/suppressor ratio was observed in 60% of the patients. In addition, the proliferative response of lymphocytes to PHA was impaired in the patients. It was observed the presence of inhibitory activity on lymphocyte function in the plasma of 33% of children with febrile seizures. These results suggest that patients with febrile seizures have an impairment of cellular immunity that may be connected with this epileptic syndrome and explain the infections observed.
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Shmagel, K. V. "DISCORDANT RESPONSE OF CD4+ T LYMPHOCYTES TO ANTIRETROVIRAL THERAPY." HIV Infection and Immunosuppressive Disorders 11, no. 1 (April 7, 2019): 16–30. http://dx.doi.org/10.22328/2077-9828-2019-11-1-16-30.
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Antiretroviral therapy (ART) in HIV infected patients generally results in the suppression of viral replication and reconstitution of CD4+ T lymphocytes cell counts. In some patients (about 20%), however, a disturbance in regeneration of immune competent cells with a background of low viral load occurs. The term «immunological nonresponders» has been used to describe this phenomenon. Discordant immune response to antiviral therapy may be caused by increasing of depletion and reducing of production of CD4+ T cells. However, mechanisms for low immune reconstitution are not currently well understood. «Immunological nonresponders» exhibit booster lymphocyte proliferation, increased immune activation and reducing of CD4+ T lymphocytes survival time in comparison with patients with concordant response to the therapy. Their immune system is characterized by more pronounced aging and exhaustion. This leads to early and frequent manifestation of AIDSrelated diseases. Besides, immunological nonresponders have an increased risk of non-AIDS-related diseases due to pronounced systemic inflammation. The objective of the present review was to highlight the important problem that is rather common on аntiretroviral therapy and to enlist the specialists to the solving of this issue.
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Andjelíc, S., A. Khanna, M. Suthanthiran, and J. Nikolić-Zugić. "Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes." Journal of Immunology 158, no. 6 (March 15, 1997): 2527–34. http://dx.doi.org/10.4049/jimmunol.158.6.2527.
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Abstract Apoptosis plays an essential role in the development and homeostasis of the immune system. During lymphocyte development, potentially autoreactive cells are eliminated via the activation of a tightly regulated cell death program(s). Similar processes operate in mature lymphocytes, to control the magnitude of the normal immune response by eliminating activated lymphocytes. However, differences in susceptibility to signal-induced apoptosis between immature and mature lymphocytes are numerous. One well-characterized example occurs in response to Ca2+ elevation: peripheral T lymphocytes are resistant, while immature thymocytes are highly susceptible, to Ca2+-mediated cell death (CMCD). In this study, we show that the immunosuppressant cyclosporin A (CsA) primes splenic lymphocytes to undergo CMCD upon ionomycin stimulation. This CsA-induced CMCD affected both T and B lymphocytes. CsA-plug Ca2+-mediated apoptosis was dissected into a two-step process: first, CsA and Ca2+ synergized to induce TGF-beta 1 secretion by B cells; and then TGF-beta 1 and Ca2+ synergistically triggered T and B lymphocyte apoptosis. Together, our results suggest that lymphocyte apoptosis may play a role in CsA-induced immunosuppression via a TGF-beta-dependent mechanism.
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Coito, Ana J., Maria De Sousa, and Jerzy W. Kupiec-Weglinski. "Fibronectin in Immune Responses in Organ Transplant Recipients." Developmental Immunology 7, no. 2-4 (2000): 239–48. http://dx.doi.org/10.1155/2000/98187.
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The immune response to an organ allograft involves perpetuation of T cell infiltration and activation. Advances in understanding the mechanisms of T cell activation have placed particular emphasis on the interactions between the T-cell receptor and antigen presenting cells, with little reference to the fact that in vivo activation occurs in the physical context of extracellular matrix proteins (ECM). Indeed, the possibility that ECM proteins may have a determining role in lymphocyte adhesion and tissue localization and function is now becoming more appreciated in view of growing evidence indicating that integrins and other T cell antigens bind ECM components, with some of these components exerting synergistic effects on T- cell activation. This review focuses on the importance of interactions between lymphocytes and fibronectin, a prominent ECM component, for cell migration and function in organ allograft recipients. It explores novel therapeutic approaches based on the assumption that fibronectin represents an active element in the process of T cell activation in the immune cascade triggered by organ transplantation.
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Mody, Christopher H., Cynthia J. Wood, Rachel M. Syme, and Jason C. L. Spurrell. "The Cell Wall and Membrane of Cryptococcus neoformans Possess a Mitogen for Human T Lymphocytes." Infection and Immunity 67, no. 2 (February 1, 1999): 936–41. http://dx.doi.org/10.1128/iai.67.2.936-941.1999.
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ABSTRACT The mechanism of human T-lymphocyte activation by the pathogenic yeast Cryptococcus neoformans has not been established. Previous investigations have suggested that C. neoformanscontains a mitogen for T lymphocytes, while other investigators have attributed lymphocyte proliferation in vitro to a recall antigen. Because of the potential importance of the mechanism of T-cell activation for our understanding of the immune response toC. neoformans, the present studies were performed to determine whether C. neoformans contains a mitogen for T lymphocytes. C. neoformans stimulates fetal blood lymphocytes to proliferate and stimulates proliferation of CD45RA+ cells from adults, indicating that it stimulates naive T cells. The T-cell response to C. neoformans was dependent upon the presence of accessory cells. However, allogeneic cells were sufficient for accessory cell function, indicating that the response was not major histocompatibility complex restricted. The percentage of T cells in the cell cycle was higher than that with the recall antigen tetanus toxoid but lower than that with the mitogenic lectin phytohemagglutinin A or the superantigenStaphylococcus enterotoxin B. Precursor frequency analysis established that 1 in 7,750 ± 2,270 T cells proliferated in response to the cryptococcal cell wall and membrane. Compared to the case for most mitogens or superantigens, the proliferative response is late and the number of T cells that enter the cell cycle and the precursor frequency are low, indicating that the mitogenic effect is modest. However, the mitogenic effect of C. neoformans should be considered when interpreting the immune response to C. neoformans, since even weak mitogens can have profound effects on host defense.
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Ceylan, Ayca, Mehmet Artac, and Hasibe Artac. "Increased PD-1 and EGFR expression levels of T lymphocytes in patients with non-small cell lung cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21018-e21018. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21018.
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e21018 Background: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are proteins that negatively regulate immune responses. Increased expression of PD-L1 in cancer cells leads to inhibition of the immune response against cancer, and causes cancer development and metastasis. Epidermal growth factor receptor (EGFR) activation upregulates PD-L1 expression in lung cancer cells and contribute to escape from immune response. In this study, we aimed to investigate the circulating T lymphocyte subsets and, PD-1 and EGFR expression levels of these cells in non-small cell lung cancer (NSCLC) progression. Methods: 40 NSCLC patients with 63.8 ± 8.0 mean age and 40 healthy controls with 60.9 ± 14.6 mean age were included in the study. In the peripheral blood samples of the patients taken at the time of diagnosis and controls, CD4+ T helper (Th) subsets (Th1, Th2, Th9, Th17, Th1Th17, CD4+ follicular T [Tfc] and peripheral T cells [Tpcs]), CD8+ cytotoxic T cell (CTL) subsets (CD8+ Tfcs and Tpcs), EGFR and PD-1 expression levels of T cells were determined by flow cytometric analysis. Results: Total lymphocyte ratio was decreased in patients with NSCLC compared to control (11.5 ± 5.2 in patients and 17.6 ± 6.1 in controls, p = 0.001), but there was no significant difference in CD3+ total T, Th and CTLs as well as their subsets (p < 0.05). Increased PD-1 expression level (mean fluorescence intensity-MFI) on total lymphocyte (p = 0.001), CD3+ T (p = 0.001), CD4+ Th (p = 0.001), CTL (p = 0.016), CD4+ Tpc (p = 0.002) and CD8+ Tpc subsets (p = 0.017) were determined in the patients compared with controls. EGFR expressions were also increased on total lymphocyte, CD3+ T, Th and Th2 cells (p = 0.034, p = 0.020, p = 0.030, respectively). 19 NSCLC patients were metastatic, while 21 patients were non-metastatic. There was no significant difference in mean age between metastatic and non-metastatic NSCLC patients. Reduced total lymphocytes and Th cells, increased Th1Th17 cells were found in metastatic NSCLC patients (p = 0.003, p = 0.046 and p = 0.022, respectively). The percentage of EGFR in CD3+ T cell and Th17 cells decreased in metastatic patients. Conclusions: This study showed the increased PD-1 and EGFR expression levels of T lymphocytes in patients with NSCLC. Cancer cells may upregulate PD-1 expression by inducing EGFR activation on lymphocytes to suppress immune responses, leading to programmed cell death of lymphocytes and a decrease in the percentage of these cells in NSCLC. Therapeutic approaches focused on changing EGFR need to be considered for the distribution of T cell subsets and EGFR expressions.
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Fleischer, Vinzenz, Michaela Friedrich, Ayman Rezk, Ulrike Bühler, Esther Witsch, Timo Uphaus, Stefan Bittner, et al. "Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS." Multiple Sclerosis Journal 24, no. 5 (April 24, 2017): 632–41. http://dx.doi.org/10.1177/1352458517703799.
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Background: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS). Objective: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study. Methods: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year under treatment. Results: Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment. Furthermore, an increased CD4/CD8 ratio ( p < 0.025) in stable patients indicated a disproportionate reduction of CD8+ T cells relative to CD4+ T cells. Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year. Conclusion: DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.
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Collins, Natalie, Jernej Godec, Lihua Zou, Martin C. Mihm, Gad Getz, and W. Nicholas Haining. "Transcriptional Hallmarks Of Tumor Infiltrating Lymphocyte Responses To Melanoma." Blood 122, no. 21 (November 15, 2013): 3491. http://dx.doi.org/10.1182/blood.v122.21.3491.3491.
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Abstract Tumor-infiltrating lymphocytes (TIL) are found in a subset of melanomas. Patients with pronounced TIL responses have an excellent prognosis, suggesting that for those patients, the infiltrating immune cells are part of an effective adaptive and/or innate response to cancer. However, the molecular features of brisk TIL infiltrates have not been analyzed in situ. Moreover, it is not clear whether the features of the immune response to melanoma are shared by other tumors. Here, we used histological grading of TIL infiltrates in melanoma samples from The Cancer Genome Atlas combined with analysis of immune signatures in transcriptional profiles from the same tumors to characterize the molecular features of the immune response to melanoma. To categorize the histological grade of immune infiltrate, we reviewed digital images of 156 melanoma samples, and assigned a TIL grade (0 - 3) based on established criteria. We found that the distribution of TIL grades in our dataset was consistent with previously published analyses. We first tested whether tumors with brisk infiltrate (TIL Grade 2 or 3) showed enrichment of immune signatures relative to those with non-brisk infiltrates (TIL Grade 0 or 1) using gene-set enrichment analysis (GSEA) with a collection of ∼2000 immune-related gene-sets manually curated from published studies of adaptive and innate immunity. We found that 493 immune signatures enriched in brisk tumors (FDR<0.25), while none enriched in non-brisk tumors, suggesting that the histological TIL grade was strongly associated with transcriptional features of an immune response. Gene-sets that enriched in tumors with brisk infiltrates included those derived from CD4 and CD8 T cells (evidenced by increased expression of T cell lineage-specific genes such as CD3G, ZAP70, CD28, TBX21, PRDM1, GZMB, PRF1); those related to monocytes (CD14); as well as Type I interferon response genes (OAS1, IFI44). Surprisingly we did not find enrichment of gene-sets related to CD8 T cell exhaustion. Instead, we found highly significant enrichment of effector CD8 T cell gene-sets that featured effector cytokines, such as IFNG and TNF, and cytokine receptors such as IL-15R and IL-2RB, genes that which are normally decreased in expression in exhausted T cells. This suggests that the transcriptional profile of brisk immune infiltrates in melanoma includes features of highly functional CD8 effector T cell responses and lacks transcriptional features of exhaustion. We next tested whether the signatures of immune response to melanoma were enriched in other tumors. We identified a core set of “TIL hallmark genes” comprised of GSEA leading-edge genes from multiple gene-sets enriched in brisk vs. non-brisk melanoma samples. We then grouped the gene expression profiles of other tumor histologies according to their expression of TIL hallmark genes using single-sample GSEA. In thyroid cancer, for example, we found that the enrichment of melanoma TIL hallmark genes was strongly correlated with the presence of lymphocyte infiltrates, suggesting that there are common features of the immune response to cancer in different tumor types. Our results show that integrated analysis of histology and gene expression profiles from melanoma samples can identify the molecular features of the TIL response. We find evidence for signatures of effective CD8 T cell responses in brisk infiltrate melanomas that are shared by other tumor types. These TIL hallmark genes may help identify molecular subsets of immunogenic tumors, providing novel outcome predictors, and opportunities to stratify immunotherapeutic treatment options. More broadly, this approach can help deconvolve tumor/host gene expression profiles and better characterize the human immune response to cancer. Disclosures: No relevant conflicts of interest to declare.
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Phipps, Warren T., Andrea M. H. Towlerton, David G. Coffey, Nixon Niyonzima, and Edus H. Warren. "T-Cell Receptor Sequencing of Kaposi Sarcoma Tumors to Identify Candidate Tumor-Reactive T Cells." Journal of Global Oncology 3, no. 2_suppl (April 2017): 45s. http://dx.doi.org/10.1200/jgo.2017.009761.
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Abstract 60 Background: Development of Kaposi sarcoma (KS) is strongly associated with immune dysfunction in the context of HIV infection, but little is known about T-lymphocyte responses against KS tumor cells or human herpesvirus-8, the viral cause of KS. Increasing evidence suggests that treatment response in KS is attributable in part to an antitumor immune response that is mediated by tumor-infiltrating lymphocytes (TIL). The aim of this work was to identify TIL characteristics that are associated with tumor regression in patients with KS who were treated with antiretroviral therapy and chemotherapy as well as to identify a molecular signature of response. Methods: High-throughput sequencing of the T-cell receptor β chain ( TRB) was used to define the repertoire of T cells that infiltrate up to two pretreatment and two post-treatment KS tumors and matched normal skin obtained from HIV-infected adults with KS who received care at the Uganda Cancer Institute. We compared TRB repertoire in serially collected tumors to identify TRB sequences carried in candidate tumor-reactive T cells. Results: TRB sequencing was performed on KS tumor and matched normal skin samples from 12 HIV-infected adults with KS who collectively demonstrated a range of treatment responses. Unique populations of T cells were identified in pretreatment tumors but not in normal skin in all patients, which suggested the presence of KS-specific T-cell responses. Durable complete response to treatment in one patient was associated with significant expansion of a small number of T-cell clones, one of which carried a TRB sequence that was associated with a public CD8+ Epstein-Barr virus–associated T-cell receptor. Conclusion: Understanding the immune response to KS through cellular and molecular dissection of TIL will provide important insights into KS biology and may ultimately guide new immune-based strategies to stage and treat this often-refractory cancer. Funding: Solid Tumor Translational Research Transformative Team Grant, Fred Hutchinson Cancer Research Center; National Institutes of Health/National Cancer Institute Grant No. K23-CA150931. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST No COIs from the authors.
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Zheng, Rongjiong, Songsong Xie, Qiong Zhang, Ling Cao, Shaniya Niyazi, Xiaobo Lu, Lihua Sun, Yan Zhou, Yuexin Zhang, and Kai Wang. "Circulating Th1, Th2, Th17, Treg, and PD-1 Levels in Patients with Brucellosis." Journal of Immunology Research 2019 (August 6, 2019): 1–15. http://dx.doi.org/10.1155/2019/3783209.
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Brucella is an intracellular infection bacterium; the pathogenesis of Brucella and chronicity of infection may be related to the immune response of T cells. T lymphocytes mainly participate in cellular immune response. The extent of different T cell subsets imbalanced and their function dysregulated in patients with brucellosis remain not explicit. We grouped patients at different stages (acute, chronic, and convalescent). The frequencies of Th1, Th2, Th17, Treg, and PD-1 (programmed cell death protein 1) in peripheral blood were examined by flow cytometry, and the expressions of T lymphocyte cytokines in serum were detected by cytometric bead array. Th1, Th17, and Treg cell immunity was predominant in the acute stage, while Th2, Th17, and Treg cell immunity was predominant in the chronic stage. The expressions of PD-1 on CD4+ and CD8+ T lymphocytes were significantly different in acute and chronic patients. The percentages of Th1 cells in convalescent patients were still higher than those in healthy controls within one year after withdrawal. The expression of T lymphocyte cytokines in serum was different in patients at different stages. These results indicate that peripheral T lymphocyte immunity was involved in patients with brucellosis and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics. The patients’ immune function had not completely recovered in a short period of time during convalescence, so long-term follow-up of convalescent patients is needed.
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Jacobs, Nathalie, Ron A. J. Chen, Caroline Gubser, Pilar Najarro, and Geoffrey L. Smith. "Intradermal immune response after infection with Vaccinia virus." Journal of General Virology 87, no. 5 (May 1, 2006): 1157–61. http://dx.doi.org/10.1099/vir.0.81556-0.
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Although Vaccinia virus (VACV) was used to eradicate smallpox by dermal vaccination, there is little information available about the immune response induced at the vaccination site. Previously, an intradermal murine model that mimics smallpox vaccination was established. Here, this model was used to investigate which leukocytes are recruited to the infected lesion and what are the kinetics of recruitment. Data presented show that VACV infection induced the infiltration of macrophages, followed by granulocytes and lymphocytes. Up to 4 days post-infection, the major lymphocyte population was TCRγδ T cells, but thereafter, there was a large recruitment of CD4+ and CD8+ T cells. Interestingly, the majority of T cells expressed the natural killer-cell marker DX5. This report is the first to characterize the local immune response sequence to VACV infection and represents a benchmark against which the responses induced by genetically modified VACVs may be compared.
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Kawabe, Takeshi, and Alan Sher. "Memory-phenotype CD4+ T cells: a naturally arising T lymphocyte population possessing innate immune function." International Immunology 34, no. 4 (December 13, 2021): 189–96. http://dx.doi.org/10.1093/intimm/dxab108.
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Abstract In conventional adaptive immune responses, upon recognition of foreign antigens, naive CD4+ T lymphocytes are activated to differentiate into effector/memory cells. In addition, emerging evidence suggests that in the steady state, naive CD4+ T cells spontaneously proliferate in response to self-antigens to acquire a memory phenotype (MP) through homeostatic proliferation. This expansion is particularly profound in lymphopenic environments but also occurs in lymphoreplete, normal conditions. The ‘MP T lymphocytes’ generated in this manner are maintained by rapid proliferation in the periphery and they tonically differentiate into T-bet-expressing ‘MP1’ cells. Such MP1 CD4+ T lymphocytes can exert innate effector function, producing IFN-γ in response to IL-12 in the absence of antigen recognition, thereby contributing to host defense. In this review, we will discuss our current understanding of how MP T lymphocytes are generated and persist in steady-state conditions, their populational heterogeneity as well as the evidence for their effector function. We will also compare these properties with those of a similar population of innate memory cells previously identified in the CD8+ T lymphocyte lineage.
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McEvoy, Leslie M., Hailing Sun, John G. Frelinger, and Eugene C. Butcher. "Anti-CD43 Inhibition of T Cell Homing." Journal of Experimental Medicine 185, no. 8 (April 21, 1997): 1493–98. http://dx.doi.org/10.1084/jem.185.8.1493.
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The homing of lymphocytes from the blood is controlled by specialized processes of lymphocyte–endothelial cell interaction. Interference with these processes offers the potential to manipulate lymphocyte traffic, and thus to modulate normal and pathologic immune and inflammatory responses. We selected antilymphocyte monoclonal antibodies (mAbs) for inhibition of lymphocyte binding in vitro to lymph node high endothelial venules (HEV), specialized vessels that support lymphocyte recruitment into lymph nodes. mAb L11 blocks T cell binding to lymph node and Peyer's patch HEV and inhibits T cell extravasation from the blood into organized secondary lymphoid tissues. In contrast, L11 has no effect on lymphocyte binding to purified vascular ligands for L-selectin, α4β7, or LFA-1, suggesting that it inhibits by a novel mechanism. The L11 antigen is CD43, a sialomucin implicated in vitro in regulation of lymphocyte activation, whose expression is often dysregulated in the Wiskott-Aldrich syndrome. CD43 represents a novel target for experimental and therapeutic manipulation of lymphocyte traffic and may help regulate T cell distribution in vivo.
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Hamra, Jena G., and Tony L. Yaksh. "Equianalgesic Doses of Subcutaneous but Not Intrathecal Morphine Alter Phenotypic Expression of Cell Surface Markers and Mitogen-induced Proliferation in Rat Lymphocytes." Anesthesiology 85, no. 2 (August 1, 1996): 355–65. http://dx.doi.org/10.1097/00000542-199608000-00018.
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Background Surgical trauma and opioids are linked with suppression of immune function. Evidence suggests a probable supraspinal action of morphine in altering immune function, although the role of spinal systems have not been evaluated. Therefore, this study compared the effect of equianalgesic doses of subcutaneous and intrathecal morphine on lymphocyte proliferative responses and phenotypic expression of lymphocyte cell surface markers in rats. Methods Equianalgesic doses of subcutaneous (10 mg/kg) or intrathecal (30 micrograms, by a chronic intrathecal catheter) morphine were given twice for 5 h (time 0 and 2.5 h). Immediately after the 5-h period or 24 h after the initial injection, spleens were harvested and lymphocytes isolated. Mitogen-induced (phytohemagglutinin, concanavalin A, pokeweed, lipopolysaccharide) lymphocyte proliferation and monoclonal antibody labeling of cell surface markers (T cell, B cell, CD4+, CD8+) were then performed. Results Subcutaneous morphine acutely suppressed lymphocyte proliferation to the mitogens phytohemagglutinin, pokeweed, and concanavalin A by 37%, 21%, and 20% respectively; however, proliferative responses returned to baseline within 24 h. Morphine treatment did not alter the response to lipopolysaccharide. The number of splenic lymphocytes also decreased, whereas the percentage of lymphocytes expressing the CD4+ marker (T helper/inducer cells) modestly increased. Intrathecal morphine did not alter lymphocyte proliferative responses, nor did it change phenotypic expression of cell surface markers. Conclusions Subcutaneous morphine inhibited lymphocyte proliferation, decreased splenic lymphocyte number, and altered phenotypic expression of cell surface markers, whereas equianalgesic doses of intrathecal morphine did not. Although these results suggest that spinal opioids may have theoretical benefits for the analgesic management of immunocompromised patients, further studies are clearly indicated.
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De Boer, R. J., P. Hogeweg, H. F. Dullens, R. A. De Weger, and W. Den Otter. "Macrophage T lymphocyte interactions in the anti-tumor immune response: a mathematical model." Journal of Immunology 134, no. 4 (April 1, 1985): 2748–58. http://dx.doi.org/10.4049/jimmunol.134.4.2748.
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Abstract In this paper we present a model of the macrophage T lymphocyte interactions that generate an anti-tumor immune response. The model specifies i) induction of cytotoxic T lymphocytes, ii) antigen presentation by macrophages, which leads to iii) activation of helper T cells, and iv) production of lymphoid factors, which induce a) cytotoxic macrophages, b) T lymphocyte proliferation, and c) an inflammation reaction. Tumor escape mechanisms (suppression, antigenic heterogeneity) have been deliberately omitted from the model. This research combines hitherto unrelated or even contradictory data within the range of behavior of one model. In the model behavior, helper T cells play a crucial role: Tumors that differ minimally in antigenicity (i.e., helper reactivity) can differ markedly in rejectability. Immunization yields protection against tumor doses that would otherwise be lethal, because it increases the number of helper T cells. The magnitude of the cytotoxic effector cell response depends on the time at which helper T cells become activated: early helper activity steeply increases the magnitude of the immune response. The type of cytotoxic effector cells that eradicates the tumor depends on tumor antigenicity: lowly antigenic tumors are attacked mainly by macrophages, whereas large highly antigenic tumors can be eradicated by cytotoxic T lymphocytes only.
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Carrera, Maria. "Immune Checkpoints Acting as Gate-keepers of T Lymphocyte Self-renewal." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 57.52. http://dx.doi.org/10.4049/jimmunol.200.supp.57.52.
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Abstract Immune checkpoint inhibition represents a promising therapeutic modality for several previously incurable cancer syndromes. Why successful T cell responses are achieved in some patients but not others is incompletely understood. Because blockade of more than one inhibitory signal is now being investigated as approach to increase the chances of therapeutic success, we investigated how combined loss of PD-1 and LAG-3 signaling in CD8+ T cells would influence a well-characterized immune response. After challenge with Vaccinia virus, T cells from mice lacking both inhibitory pathways underwent a more vigorous primary effector cell response but were severely defective during a secondary challenge. During modeled T cell activation, immune checkpoint inhibition resulted in greater production of irreversibly differentiated effector cell progeny, but this came at the expense of accelerated depletion of self-renewing progenitor cells. Pharmacological interventions that impede anabolism-associated signaling were able to correct progenitor cells loss in the face of checkpoint inhibition. Unleashing greater and greater T cell activation may result in regenerative failure of critical clones. By fostering the expansion of self-renewing progenitors, reversible agents that dampen T cell signal strength might paradoxically improve durability of immune checkpoint inhibition.
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Beverley, Peter C. L., and Mala K. Maini. "Differences in the regulation of CD4 and CD8 T–cell clones during immune responses." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1395 (March 29, 2000): 401–6. http://dx.doi.org/10.1098/rstb.2000.0580.
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The functional units of immune response are lymphocyte clones. Analysis of lymphocyte life span in vivo shows that the overall turnover of CD4 and CD8 lymphocytes does not differ greatly. Recently, molecular methods have been developed which allow a global analysis of T–cell clones responding to an antigen in vivo . We have used a sensitive, modified heteroduplex analysis to follow T–cell clones responding to Epstein–Barr virus in acute infectious mononucleosis (AIM). Strikingly, all the many large clones detected in freshly isolated AIM blood were found within the CD8 fraction. CD4 clonal populations responding to the soluble recall antigen tetanus toxoid could only be detected after in vitro re–stimulation. These data imply that CD4 responses may be more polyclonal than those of CD8 cells and that the size of CD4 clones is more tightly regulated. Several molecular mechanisms may contribute to this. Up–regulation of telomerase allows very large expansions of CD8 cells to occur without exhaustion of proliferative capacity.
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Norimine, Junzo, Juan Mosqueda, Carlos Suarez, Guy H. Palmer, Terry F. McElwain, Gabriel Mbassa, and Wendy C. Brown. "Stimulation of T-Helper Cell Gamma Interferon and Immunoglobulin G Responses Specific for Babesia bovis Rhoptry-Associated Protein 1 (RAP-1) or a RAP-1 Protein Lacking the Carboxy-Terminal Repeat Region Is Insufficient To Provide Protective Immunity against Virulent B. bovis Challenge." Infection and Immunity 71, no. 9 (September 2003): 5021–32. http://dx.doi.org/10.1128/iai.71.9.5021-5032.2003.
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ABSTRACT Rhoptry-associated protein 1 (RAP-1) is a targeted vaccine antigen for Babesia bovis and Babesia bigemina infections of cattle. The 60-kDa B. bovis RAP-1 is recognized by antibodies and T lymphocytes from cattle that recovered from infection and were immune to subsequent challenge. Immunization with native or recombinant protein was reported to reduce parasitemias in challenged animals. We recently reported that the NT domain of B. bovis RAP-1 contained immunodominant T-cell epitopes, whereas the repeat-rich CT domain was less immunostimulatory for T lymphocytes from cattle immune to B. bovis. The present study was therefore designed to test the hypothesis that the NT region of RAP-1, used as a vaccine with interleukin-12 and RIBI (catalog no. R-730; RIBI Immunochem Research, Inc., Hamilton, Mont. [now Corixa, Seattle, Wash.]) adjuvant to induce a type 1 response, would prime calves for antibody and T-helper cell responses comparable to or greater than those induced by full-length RAP-1 containing the C-terminal repeats. Furthermore, a type 1 immune response to RAP-1 was hypothesized to induce protection against challenge. Following four inoculations of either recombinant full-length RAP-1 or RAP-1 NT protein, RAP-1-specific immunoglobulin G (IgG) titers, T-lymphocyte proliferation, and gamma interferon production were similar. Similar numbers of NT region peptides were recognized. However, in spite of the presence of strong RAP-1-specific IgG and CD4+-T-lymphocyte responses that were recalled upon challenge, neither antigen stimulated a protective immune response. We conclude that successful priming of calves with recombinant RAP-1 and adjuvants that elicit strong Th1 cell and IgG responses is insufficient to protect calves against virulent B. bovis challenge.