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1
Y, Elshimali. "Chimeric Antigen Receptor T-Cell Therapy (Car T-Cells) in Solid Tumors, Resistance and Success." Bioequivalence & Bioavailability International Journal 6, no. 1 (2022): 1–6. http://dx.doi.org/10.23880/beba-16000163.
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CARs are chimeric synthetic antigen receptors that can be introduced into an immune cell to retarget its cytotoxicity toward a specific tumor antigen. CAR T-cells immunotherapy demonstrated significant success in the management of hematologic malignancies. Nevertheless, limited studies are present regarding its efficacy in solid and refractory tumors. It is well known that the major concerns regarding this technique include the risk of relapse and the resistance of tumor cells, in addition to high expenses and limited affordability. Several factors play a crucial role in improving the efficacy of immunotherapy, including tumor mutation burden (TMB), microsatellite instability (MSI), loss of heterozygosity (LOH), the APOBEC Protein Family, tumor microenvironment (TMI), and epigenetics. In this minireview, we address the current and future applications of CAR T-Cells against solid tumors and their measure for factors of resistance and success.
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Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "CAR T Cells: Precision Cancer Immunotherapy." Indonesian Biomedical Journal 10, no. 3 (December 28, 2018): 203–16. http://dx.doi.org/10.18585/inabj.v10i3.635.
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BACKGROUND: Current cancer drugs and treatments are aiming at eradicating tumor cells, but often are more toxic then effective, killing also the normal cells and not selectively the tumor cells. There is good personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity, which called adoptive cell therapy (ACT). A review of the unique biology of T cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities.CONTENT: Chimeric antigen receptors (CAR) are recombinant receptors which provide both antigen-binding and T cell-activating functions. Many kind of CARs has been reported for the past few years, targeting an array of cell surface tumor antigens. Their biologic functions have extremely changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. The combination of CARs with costimulatory ligands, chimeric costimulatory receptors, or cytokines can be done to further enhance T cell potency, specificity and safety. CARs reflects a new class of drugs with exciting potential for cancer immunotherapy.SUMMARY: CAR-T cells have been arising as a new modality for cancer immunotherapy because of their potent efficacy against terminal cancers. They are known to exert higher efficacy than monoclonal antibodies and antibodydrug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors.KEYWORDS: chimeric antigen receptor, CAR T cells, adoptive cell therapy, ACT, T cell receptor, TCR, cancer, immunotherapy
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Steverding, Dietmar. "Cycle Numbers of Cell Surface Recycling Receptors." Receptors 2, no. 2 (June 6, 2023): 160–65. http://dx.doi.org/10.3390/receptors2020010.
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The cycle number (nc) of a recycling receptor is defined as the average number of round trips (cell surface–endosome–cell surface) the receptor can make before it is degraded. This characteristic parameter of recycling receptors can be easily determined from the receptor’s half-life (t½, the time in which 50% of the receptor is degraded) and cycling time (Tc, the time a receptor needs to complete a round trip). Relationship analyses revealed that nc increases linearly with increasing t½ and decreases exponentially with increasing Tc. For commonly observed t½ and Tc values, it was calculated that recycling receptors have nc values of <300. In addition, it was found that recycling receptors in cancer cells have generally smaller nc values (<100), whereas recycling receptors in normal cells have larger nc values (>100). Based on this latter finding, the cycle number nc may be a useful criterion for distinguishing between cancer and normal cells.
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Coico, R. F., B. Xue, D. Wallace, B. Pernis, G. W. Siskind, and G. J. Thorbecke. "T cells with receptors for IgD." Nature 316, no. 6030 (August 1985): 744–46. http://dx.doi.org/10.1038/316744a0.
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Klein, Thomas W., Cathy Newton, Kellie Larsen, Joe Chou, Izabella Perkins, Lily Lu, Liang Nong, and Herman Friedman. "Cannabinoid receptors and T helper cells." Journal of Neuroimmunology 147, no. 1-2 (February 2004): 91–94. http://dx.doi.org/10.1016/j.jneuroim.2003.10.019.
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Rossig, Claudia, Catherine M. Bollard, Jed G. Nuchtern, Cliona M. Rooney, and Malcolm K. Brenner. "Epstein-Barr virus–specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy." Blood 99, no. 6 (March 15, 2002): 2009–16. http://dx.doi.org/10.1182/blood.v99.6.2009.
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Abstract Primary T cells expressing chimeric receptors specific for tumor or viral antigens have considerable therapeutic potential. Unfortunately, their clinical value is limited by their rapid loss of function and failure to expand in vivo, presumably due to the lack of costimulator molecules on tumor cells and the inherent limitations of signaling exclusively through the chimeric receptor. Epstein-Barr virus (EBV) infection of B lymphocytes is near universal in humans and stimulates high levels of EBV-specific helper and cytotoxic T cells, which persist indefinitely. Our clinical studies have shown that EBV-specific T cells generated in vitro will expand, persist, and function for more than 6 years in vivo. We now report that EBV-specific (but not primary) T cells transduced with tumor-specific chimeric receptor genes can be expanded and maintained long-term in the presence of EBV-infected B cells. They recognize EBV-infected targets through their conventional T-cell receptor and tumor targets through their chimeric receptors. They efficiently lyse both. EBV-specific T cells expressing chimeric antitumor receptors may represent a new source of effector cells that would persist and function long-term after their transfer to cancer patients.
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Sato, Noriko, Richard N. Bamford, Bonita R. Bryant, Yutaka Tagaya, and Thomas A. Waldmann. "Accessory cells precondition naive T cells and regulatory T cells for cytokine-mediated proliferation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 164.02. http://dx.doi.org/10.4049/jimmunol.210.supp.164.02.
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Abstract Naïve T cells and regulatory T cells, when purified, do not proliferate to the common cytokine receptor γ-chain family cytokines interleukin (IL)-2, IL-7 or IL-15, despite their expression of cognate cytokine receptors. Cell-to-cell contact with dendritic cells (DCs) enabled proliferation of the T cell to these cytokines, independent of antigen recognition or T cell receptor stimulation. This effect lasted after separation of T cells from DCs, enabling enhanced proliferation of the T cells in mice depleted of DCs. We propose calling this a “preconditioning effect”. Interestingly, IL-2 alone was sufficient to induce phosphorylation and nuclear translocation of STAT5 in T cells, but could not activate MAPK and AKT pathways and failed to induce transcription of IL-2-target genes. Preconditioning was necessary to activate these two pathways, and induced weak Ca 2+mobilization independent of calcium release-activated channels. When preconditioning was combined with IL-2, full activation of downstream mTOR, 4E-BP1 hyperphosphorylation and prolonged S6 phosphorylation occurred, and T cells underwent proliferation. Collectively, accessory cells provide T cell preconditioning, a unique activation mechanism, controlling cytokine-mediated proliferation of T cells.
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Suzuki, T., and M. D. Cooper. "Comparison of the expression of IL 2 receptors by human T and B cells: induction by the polyclonal mitogens, phorbol myristate acetate, and anti-mu antibody." Journal of Immunology 134, no. 5 (May 1, 1985): 3111–19. http://dx.doi.org/10.4049/jimmunol.134.5.3111.
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Abstract It is well established that IL 2 plays an important role in the proliferative response of T cells. Activated B cells were also recently found to express IL 2 receptors. The present studies were designed to compare qualitative, quantitative, and functional aspects of IL 2 receptor expression by activated T and B cells. Phorbol myristate acetate (PMA)-activated human T and small resting B cells and enhanced the expression of HLA-DR, HLA-DC/DS, and transferrin receptors while reducing Leu-4 antigen expression by T cells and IgM and IgD expression on B cells. PMA induced both T and B cells to express functional IL 2 receptors before cellular proliferation. Immune interferon did not participate in this induction. The m.w. of the IL 2 receptors expressed by activated T and B cells was identical: 54,000 to 59,000. Several differences were noted in the expression of IL 2 receptors by activated T and B cells on stimulation with PMA; T cells expressed IL 2 receptors sooner than B cells and in higher density, and the enhanced proliferative response of T cells to IL 2 was more difficult to inhibit with antibody to IL 2 receptors. In addition, IL 2 enhanced the expression of transferrin receptors by activated T cells but did not have a similar effect on activated B cells. Small B cells from the blood could also be induced by a mitogenic monoclonal anti-IgM antibody to express functional IL 2 receptors. Relatively large B cells in fresh blood samples were found to express functional IL 2 receptors and were capable of a modest proliferative response to IL 2. The intensity of the IL 2 receptor expression and the proliferative response by large B cells were enhanced by PMA stimulation. The data suggest that IL 2 receptors may play an auxiliary role in the B cell proliferative response and that IL 2 may exert its effect at a late phase in the B cell activation process.
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Scheurich, P., B. Thoma, U. Ucer, and K. Pfizenmaier. "Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses." Journal of Immunology 138, no. 6 (March 15, 1987): 1786–90. http://dx.doi.org/10.4049/jimmunol.138.6.1786.
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Abstract The expression of specific tumor necrosis factor (TNF) membrane receptors and biological effects of recombinant TNF (rTNF)-alpha on normal human T lymphocytes were studied. Although resting T cells lacked specific binding capacity for rTNF-alpha, high affinity (Kd 70 pM) TNF receptors were de novo induced upon primary activation of T cells. Comparison of TNF receptor expression with that of high affinity interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) receptors, respectively, revealed similarities to IL 2-receptor expression with respect to kinetics of induction. However, maximum expression of TNF receptors (approximately equal to 5000/cell at day 6) and subsequent decline occurred approximately 3 days after the peak of IL 2-receptor expression. In contrast, no change in the expression of IFN-gamma receptors (Kd 10 pM, 300 to 400 receptors/cell) was found in the course of T cell activation. On activated TNF receptor positive T cells, TNF-alpha exerted multiple stimulatory activities. Thus TNF increased the expression of HLA-DR antigens and high affinity IL 2 receptors. As a consequence, TNF-treated T cells showed an enhanced proliferative response to IL 2. Moreover, TNF-alpha was effective as a co-stimulator of IL 2-dependent IFN-gamma production. These data indicate that TNF-alpha may regulate growth and functional activities of normal T cells.
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Aune, T. M., K. M. McGrath, T. Sarr, M. P. Bombara, and K. A. Kelley. "Expression of 5HT1a receptors on activated human T cells. Regulation of cyclic AMP levels and T cell proliferation by 5-hydroxytryptamine." Journal of Immunology 151, no. 3 (August 1, 1993): 1175–83. http://dx.doi.org/10.4049/jimmunol.151.3.1175.
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Abstract The neurotransmitter, serotonin (5-hydroxytryptamine, 5HT), has been shown to affect function of cells of the immune system. More recently, specific 5HT receptors have been identified and partially characterized on Jurkat cells. Results presented here characterize the receptor on Jurkat cells as the 5HT1a receptor subtype and show that mitogen-activated but not resting human T cells also express the 5HT1a receptor subtype. Analysis of mRNA in Jurkat cells and activated and resting T cells by PCR or by Northern analysis revealed the presence of 5HT1a receptor. Pharmacologic analysis of this receptor demonstrated that the receptors on Jurkat cells and activated T cells are similar to each other and that they resemble the 5HT1a receptor found in the brain. Analysis of the second messenger pathways activated by the 5HT1a receptor show that ligand-binding to the Jurkat cell 5HT1a receptor results in elevation of intracellular inositol phosphates and Ca2+ and that ligand binding to the 5HT1a receptor on activated T cells modulated intracellular levels of cAMP.
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Kamiya, Takahiro, Desmond Wong, Yi Tian Png, and Dario Campana. "A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells." Blood Advances 2, no. 5 (March 5, 2018): 517–28. http://dx.doi.org/10.1182/bloodadvances.2017012823.
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Key Points Newly designed PEBLs prevent surface expression of T-cell receptor in T cells without affecting their function. Combined with chimeric antigen receptors, PEBLs can rapidly generate powerful antileukemic T cells without alloreactivity.
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Posnett, D. N., A. Gottlieb, J. B. Bussel, S. M. Friedman, N. Chiorazzi, Y. Li, P. Szabo, N. R. Farid, and M. A. Robinson. "T cell antigen receptors in autoimmunity." Journal of Immunology 141, no. 6 (September 15, 1988): 1963–69. http://dx.doi.org/10.4049/jimmunol.141.6.1963.
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Abstract Three mAb to variable region determinants of the alpha/beta-chain TCR were used to detect discrete populations of peripheral blood T cells. T cells sharing a TCR determinant defined by such an antibody presumably use the same or similar TCR V or J genes for their alpha- or beta-chains. Thus analysis with these mAb provides a tool to investigate TCR gene usage and expression. Since autoantigen specific T cells may play an important role in initiating autoimmune diseases, TCR were analyzed in different autoimmune diseases and control groups including rheumatoid arthritis, Graves disease, idiopathic thrombocytopenic purpura, psoriasis, SLE, insulin-dependent diabetes mellitus, and in nonautoimmune control diseases and normals. Purified T cells were stained by indirect immunofluorescence with three mAb to TCR variable regions: mAb S511 stains 1.8 +/- 0.9% (mean +/- 2 SD), mAb C37 stains 3.4 +/- 1.5% and mAb OT145 stains from 0 to 6% of T cells from normal donors. Several individuals were identified with expanded subsets of positive T cells. One patient with adult ITP followed during a 12-mo period consistently had elevated percentages of T cells staining with the mAb OT145 (15.9 to 24.5%). These cells were found to be exclusively CD8+. By Southern blotting DNA prepared from these OT145+, CD8+ cells, but not DNA from the patient's OT145- T cells, revealed a clonal rearrangement using a beta-chain C region probe. Thus this patient had a monoclonal expansion of CD8+, OT145+ cells. Hyperexpression of a TCR variable region, as defined by the available mAb, could not be associated with any of the diseases studied. Examination of T cells at the site of autoimmunity, such as T cells from rheumatoid arthritis synovial fluid, revealed normal percentages of cells staining with these mAb. Immunoperoxidase staining of psoriatic lesional skin showed no striking enrichment of T cells bearing one or the other TCR type.
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Wu, Ling, Qianru Wei, Joanna Brzostek, and Nicholas R. J. Gascoigne. "Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells." Cellular & Molecular Immunology 17, no. 6 (May 25, 2020): 600–612. http://dx.doi.org/10.1038/s41423-020-0470-3.
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Kim, Chang H., Jeeho Lee, and Seung G. Kang. "Developmental and antigen-driven switches in the trafficking receptors of FoxP3+ regulatory T cells (99.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S194. http://dx.doi.org/10.4049/jimmunol.178.supp.99.2.
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Abstract FoxP3+ regulatory T cells play important roles in immune regulation and tolerance. There is an increasing body of evidence that the migration ability of FoxP3+ T cells is important for their regulatory functions at effector tissue sites. We investigated the two different trafficking receptor switches of FoxP3+ T cells occurring in the thymus and secondary lymphoid tissues. The first trafficking receptor switch in the thymus is developmentally programmed: Precursors of FoxP3+ cells undergo the first trafficking receptor switch from CCR8/CCR9 to CXCR4 and then finally to CCR7, generating mostly homogeneous CD62L+CCR7+ FoxP3+ T cells. The recent thymic emigrant CD62L+CCR7+ FoxP3+ T cells are programmed to migrate to secondary lymphoid tissues. The CD62L+CCR7+ FoxP3+ T cells undergo the second switch in trafficking receptors in an antigen-dependent manner. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3+ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9 and CXCR5. FoxP3+ cells undergo the second switch to selected non-lymphoid tissue homing receptors at highly accelerated rates. This results in generation of FoxP3+ T cells with unconventionally efficient migratory capacity to major non-lymphoid tissues such as intestinal lamina propria and bone marrow. Importantly, this accelerated switch of FoxP3+ T cells is conserved in both men and mice. The two switches in homing receptors are though to be important for effective distribution and differentiation-dependent effector functions of FoxP3+ regulatory T cells.
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Umemura, Masayuki, Masatoshi Yamasaki, Toshiki Tamura, and Goro Matsuzaki. "Dispensable role of chemokine receptors in migration of mycobacterial antigen-specific CD4+ T cells into mycobacteria-infected lung." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 156.34. http://dx.doi.org/10.4049/jimmunol.204.supp.156.34.
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Abstract Mycobacterial antigen-specific CD4+ Th1 cells have a pivotal role in protective immunity against mycobacterial infections, including pulmonary tuberculosis. In the course of infection, Th1 cells differentiate in the lung-draining lymph nodes and migrate into the infected lung. Chemokine receptors on T cells are involved in T cell migration into the intestine and skin. However, the role of chemokine receptors in the migration of CD4+ T cells into the lung has not yet been determined. To address this issue, the role of chemokine receptors in T cell migration into the mycobacteria-infected lung was analyzed using mycobacterial Ag85B peptide 25-specific T cell receptor-transgenic (P25) CD4+ T cells. P25 T cells in the Mycobacterium bovis BCG-infected lung and lung-draining mediastinal lymph nodes (MedLN) expressed the chemokine receptors, CCR5, CCR6, CXCR3, and CXCR5, which bind chemokines produced by the BCG-infected lung. To further analyze the role of chemokine receptors in the migration of BCG-primed P25 T cells into the lung and medLN, P25 T cells were adoptively transferred into BCG-infected wild-type mice and their migration into the lung was monitored. Unexpectedly, blocking chemokine receptor function with pertussis toxin, a G-protein inhibitor, failed to suppress migration of T cells into the infected lung. However, the treatment completely blocked migration of the MedLN P25 T cells into the recipient lymph node. These results suggest that the interaction of chemokine receptors on mycobacterial antigen-specific Th1 cells with chemokines is dispensable for their migration into the mycobacteria-infected lung.
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Baldanzi, Gianluca. "Immune Checkpoint Receptors Signaling in T Cells." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3529. http://dx.doi.org/10.3390/ijms23073529.
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The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved.
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Kochenderfer, James N. "Chimeric Antigen Receptors/Genetically Modified T-Cells." Blood 128, no. 22 (December 2, 2016): SCI—37—SCI—37. http://dx.doi.org/10.1182/blood.v128.22.sci-37.sci-37.
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Multiple myeloma (MM) is a usually incurable malignancy of plasma cells. While the therapy of MM has improved greatly in the past 15 years, therapies with novel mechanisms of action are needed for MM. Allogeneic stem cell transplantation has been shown to have a potent anti-myeloma effect, and allogeneic donor lymphocyte infusions can cause remissions of MM. These results from allogeneic transplantation show that MM can be vulnerable to cellular immunotherapies, but allogeneic transplants have substantial rates of mortality and morbidity. Anti-CD19 CAR T cells have been shown to have powerful activity against B-cell malignancies. The success of anti-CD19 CAR T cells against B-cell malignancies has motivated investigators to develop genetically-modified T-cell therapies for MM. CD19 has been targeted as a therapy for multiple myeloma. A clinical trial of anti-CD19 CAR T cells for MM is underway. Part of the rationale for targeting CD19 is that CD19 might be expressed on a myeloma stem cell, which might be a mature B cell. The NY-ESO antigen has been targeted by human-leukocyte-antigen-restricted T cells in a clinical trial enrolling MM patients. B-cell maturation antigen (BCMA) is expressed by most cases of MM. We conducted the first-in-humans clinical trial of CAR T cells targeting BCMA at the National Cancer Institute. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells on this dose-escalation trial. Among the 6 patients treated on the lowest two dose levels, limited anti-myeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9x106 CAR+T cells/kg bodyweight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM with 80% bone marrow plasma cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T-cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients also had prolonged cytopenias. In summary, our findings demonstrated strong anti-myeloma activity of CAR-BCMA T cells. One of the best attributes of the CAR T-cell field is that there are multiple avenues for improving CAR T-cell therapies. New CAR designs are being tested. Any part of the CAR might be improved including development of new fully-human single chain variable fragments (scFv) for the antigen-recognition component of the CAR, testing different hinge and transmembrane domains, and defining the optimal costimulatory moieties. Another avenue for improving CAR T-cell therapies is improving T-cell culture methods. Optimizing clinical application of CAR T cells, especially enhancing toxicity management, is another important avenue of improving CAR T-cell therapies. Finally, identifying new CAR target antigens is a critically important area of CAR research. In summary, genetically-modified T cells hold great promise to make a profound improvement in the therapy of multiple myeloma. Disclosures Kochenderfer: bluebird bio: Patents & Royalties, Research Funding; Kite Pharma: Patents & Royalties, Research Funding.
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Modlin, Robert L., Michael B. Brenner, Michael S. Krangel, Allan D. Duby, and Barry R. Bloom. "T-cell receptors of human suppressor cells." Nature 329, no. 6139 (October 1987): 541–45. http://dx.doi.org/10.1038/329541a0.
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Tordai, A., J. W. Fenton, T. Andersen, and E. W. Gelfand. "Functional thrombin receptors on human T lymphoblastoid cells." Journal of Immunology 150, no. 11 (June 1, 1993): 4876–86. http://dx.doi.org/10.4049/jimmunol.150.11.4876.
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Abstract Human alpha-thrombin stimulated five different T lymphoblastoid cell lines to increase intracellular free Ca2+ concentrations, whereas five B cell lines did not similarly respond. The T cell intracellular free Ca2+ increased rapidly, plateaued within 10 to 20 s, and then declined without any measurable sustained intracellular free Ca2+ elevation. Liberation of inositol trisphosphate peaked within 60 s, and a rapid and sustained activation of protein kinase C was induced. The thrombin-specific inhibitor, hirudin, completely blocked the response to alpha-thrombin. Catalytically inactivated forms of alpha-thrombin failed to stimulate the T cells, whereas trypsin, gamma-thrombin (which lacks fibrinogen clotting activity), or the synthetic 14-amino acid thrombin receptor-activation peptide stimulated T cells, but required approximately 10-, approximately 15-, or approximately 100-fold higher concentrations, respectively, when compared to alpha-thrombin. Stimulation by thrombin receptor-activation peptide was desensitized by alpha-thrombin, and vice versa, but alpha-thrombin did not desensitize stimulation by mAb to the TCR/CD3 Ag. The presence of the receptor on T but not on B cells was confirmed by flow-cytometric analysis using a mAb against the human thrombin receptor. These findings demonstrate functional thrombin receptors on T lymphoblastoid cells that may be capable of activating the cells, independently of an ongoing immune response.
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Zhang, Peng-Fei, Chuang Wang, Le Zhang, and Qiu Li. "Reversing chemokine/chemokine receptor mismatch to enhance the antitumor efficacy of CAR-T cells." Immunotherapy 14, no. 6 (April 2022): 459–73. http://dx.doi.org/10.2217/imt-2021-0228.
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Currently, the antitumor efficacy of chimeric antigen receptor T cells in solid tumors is modest. Both chemokines and their receptors play a key role in the proliferation of cancer cells, tumor angiogenesis, organ-selective metastasis and migration of immune cells to solid tumors. Unfortunately, frequent chemokine/chemokine receptor ‘mismatch’ between effector cells and the tumor microenvironment results in inefficient T-cell infiltration and antitumor efficacy. Thus, reversing the ‘mismatch’ of chemokines and chemokine receptors appears to be a promising method for promoting T-cell infiltration into the tumor and enhancing their antitumor efficacy. In this review, we discuss functions of the chemokine/chemokine receptor axis in cancer immunity and the current understanding, challenges and prospects for improving the effect of chimeric antigen receptor T cells by reversing the mismatch between chemokines and chemokine receptors.
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Cameron, W., K. Doyle, and R. E. Rocklin. "Histamine type I (H1) receptor radioligand binding studies on normal T cell subsets, B cells, and monocytes." Journal of Immunology 136, no. 6 (March 15, 1986): 2116–20. http://dx.doi.org/10.4049/jimmunol.136.6.2116.
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Abstract We have documented a single, specific binding site for [3H]pyrilamine on normal human T helper, T suppressor, B cells, and monocytes. The binding of the radioligand to its receptor is reversible with cold H1 antagonist, saturates at 40 to 60 nM, and binding equilibrium is achieved in 2 to 4 min. Using a computer program (Ligand), we calculated the dissociation constants, binding capacities, and numbers of receptors per cell for each of the different cell types. Monocytes were found to have the highest affinity (mean KD +/- SD; 3.8 +/- 4.8 nM) for [3H]pyrilamine, followed by T helper cells (KD = 5.0 +/- 6.6 nM), B cells (KD = 14.2 +/- 2.0 nM), and T suppressor cells (KD = 44.6 +/- 49.4 nM). T suppressor cells were found to express the higher number of H1 receptors per cell (35,697 +/- 15,468), followed by B cells (10,732 +/- 9060), T helper cells (6838 +/- 8167), and monocytes (5589 +/- 2266). The kinetics of binding for this radioligand was carried out in resting and mitogen-stimulated T cells over a 48-hr period. We found that the binding affinity for [3H]pyrilamine increased over the 48-hr period, whereas the number of receptors per T cell was essentially unchanged. In contrast, T cells stimulated with Con A or PHA were shown to have a greater than fourfold increase in the number of receptors per cell, whereas the binding affinity for [3H]pyrilamine decreased over the 48-hr period. Preincubation of T cells with unlabeled histamine before carrying out the radioligand binding assay resulted in a decrease in the binding affinity of the receptors to [3H]pyrilamine, but the number of receptors per cell did not change significantly. Although the function of H1 receptors on T cells, B cells, and monocytes has not been completely defined, this receptor has the potential of playing an important role in modulating the immune response.
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Rabin, Ronald L., Matthew K. Park, Fang Liao, Ruth Swofford, David Stephany, and Joshua M. Farber. "Chemokine Receptor Responses on T Cells Are Achieved Through Regulation of Both Receptor Expression and Signaling." Journal of Immunology 162, no. 7 (April 1, 1999): 3840–50. http://dx.doi.org/10.4049/jimmunol.162.7.3840.
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Abstract To address the issues of redundancy and specificity of chemokines and their receptors in lymphocyte biology, we investigated the expression of CC chemokine receptors CCR1, CCR2, CCR3, CCR5, CXCR3, and CXCR4 and responses to their ligands on memory and naive, CD4 and CD8 human T cells, both freshly isolated and after short term activation in vitro. Activation through CD3 for 3 days had the most dramatic effects on the expression of CXCR3, which was up-regulated and functional on all T cell populations including naive CD4 cells. In contrast, the effects of short term activation on expression of other chemokine receptors was modest, and expression of CCR2, CCR3, and CCR5 on CD4 cells was restricted to memory subsets. In general, patterns of chemotaxis in the resting cells and calcium responses in the activated cells corresponded to the patterns of receptor expression among T cell subsets. In contrast, the pattern of calcium signaling among subsets of freshly isolated cells did not show a simple correlation with receptor expression, so the propensity to produce a global rise in the intracellular calcium concentration differed among the various receptors within a given T cell subset and for an individual receptor depending on the cell where it was expressed. Our data suggest that individual chemokine receptors and their ligands function on T cells at different stages of T cell activation/differentiation, with CXCR3 of particular importance on newly activated cells, and demonstrate T cell subset-specific and activation state-specific responses to chemokines that are achieved by regulating receptor signaling as well as receptor expression.
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Meeks, Christian Matthew, and Christopher G. Horton. "Modulation of CD4+ T cell polarization using non-canonical co-receptors." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 150.15. http://dx.doi.org/10.4049/jimmunol.198.supp.150.15.
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Abstract CD4+ T helper cells are a diverse group of cells promoting target cell death and production of antibodies. These cells acquire one of several fates following signals through the T cell receptor, co-receptors, and cytokines. The cytokine requirements inducing the polarization of T cell fate has been heavily evaluated and reasonably well defined. However, the influence provided by co-receptors has not been completely elucidated. Traditionally, in vitro T cell polarization assays utilize CD28 stimulation as the primary co-receptor signal required for differentiation. Others have observed the importance of supplementary co-receptors in activation of T helper cells, though little is known about their function in early stage polarization. We hypothesized that the addition of signaling through supplemental co-receptors would alter T helper cell polarization. To conduct these studies, we isolated naïve T cells and polarized them towards Th1 or Tfh fates in the presence or absence of recombinant B7-DC Fc chimera or recombinant B7-H4 Fc chimera. We observed a significant and selective alteration in T helper cell polarization in the presence of these non-canonical co-receptors. These data suggest a complex interplay between cytokine and co-receptor signals that cooperate for robust Th cell polarization. Furthermore, these findings illustrate the potential for novel mechanisms of T cell manipulation for vaccine design and treatment of T cell-mediated diseases.
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Frydrychowicz, Magdalena, Maciej Boruczkowski, Agata Kolecka-Bednarczyk, Renata Jenek, Joanna Rosołowska, Agnieszka Pluto-Prądzyńska, and Grzegorz Dworacki. "Characteristics of Regulatory T cells." Journal of Medical Science 85, no. 4 (December 29, 2016): 323–26. http://dx.doi.org/10.20883/jms.2016.175.
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Regulatory T cells (Tregs) is heterogenic subpopulation of T cells that is able to suppress function of effector cells during the immune response. Among them are natural (nTreg) and induced Treg (Tr1, Th3, CD4+CD25-). CD25, CD45Ro, CD152, GITR, LAG-3, several adhesion molecules, chemokine receptors as well as Toll-like receptors are present on the surface of Treg. Mechanism of suppression used by nTreg is not completely understood.
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Frydrychowicz, Magdalena, Maciej Boruczkowski, Agata Kolecka-Bednarczyk, Renata Jenek, Joanna Rosołowska, Agnieszka Pluto-Prądzyńska, and Grzegorz Dworacki. "Characteristics of Regulatory T cells." Journal of Medical Science 85, no. 4 (December 29, 2016): 323. http://dx.doi.org/10.20883/175.
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Regulatory T cells (Tregs) is heterogenic subpopulation of T cells that is able to suppress function of effector cells during the immune response. Among them are natural (nTreg) and induced Treg (Tr1, Th3, CD4+CD25-). CD25, CD45Ro, CD152, GITR, LAG-3, several adhesion molecules, chemokine receptors as well as Toll-like receptors are present on the surface of Treg. Mechanism of suppression used by nTreg is not completely understood.
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Portilla, Didier, and Mark D. Okusa. "T cells and T-cell receptors in acute renal failure." Kidney International 69, no. 2 (January 2006): 208–10. http://dx.doi.org/10.1038/sj.ki.5000128.
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Kempkes, B., E. Palmer, S. Martin, A. von Bonin, K. Eichmann, B. Ortmann, and H. U. Weltzien. "Predominant T cell receptor gene elements in TNP-specific cytotoxic T cells." Journal of Immunology 147, no. 8 (October 15, 1991): 2467–73. http://dx.doi.org/10.4049/jimmunol.147.8.2467.
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Abstract H-2b class I-restricted, TNP-specific CTL clones were obtained by limiting dilution cloning of either short term polyclonal CTL lines or spleen cells of TNP-immunized mice directly ex vivo. Sequence analyses of mRNA coding for TCR alpha- and beta-chains of 11 clones derived from CTL lines from individual C57BL/6 mice revealed that all of them expressed unique but clearly nonrandom receptor structures. Five alpha-chains (45%) employed V alpha 10 gene elements, and four of those (36%) were associated with J beta 2.6-expressing beta-chains. The alpha-chains from these four TCR, moreover, contained an acidic amino acid in position 93 of their N or J region-determined sequences. Clones isolated directly from spleen cells carried these types of receptors at lower frequency, 27% V alpha 10 and 19% J beta 2.6, indicating that bulk in vitro cultivation on Ag leads to selection for these particular receptors. However, even in TNP-specific CTL cloned directly ex vivo, V alpha 10 usage was increased about fivefold over that in Ag-independently activated T cells in H-2b mice (4 to 5%). The selection for V alpha 10/J beta 2.6-expressing cells was obtained repeatedly in other TNP-specific CTL lines from C57BL/6 mice but not in FITC-specific CTL from the same strain or in TNP-specific CTL lines from B10.BR (H-2k) or B10.D2 (H-2d) mice. We conclude from this (a) that the selection for V alpha 10/J beta 2.6+ T cells is driven by the complementarity of these receptors to a combination of TNP and MHC epitopes and (b) that predominant receptor structures reflect the existence of a surprisingly limited number of "T cell-relevant" hapten determinants on the surface of covalently TNP-modified cells.
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Cardarelli, P. M., and M. D. Pierschbacher. "Identification of fibronectin receptors on T lymphocytes." Journal of Cell Biology 105, no. 1 (July 1, 1987): 499–506. http://dx.doi.org/10.1083/jcb.105.1.499.
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We report the identification of fibronectin receptors on thymocytes and T lymphoma cells. Affinity chromatography of extracts of the T cell lymphoma, WR16.1, on a fibronectin-Sepharose column combined with specific elution using a synthetic peptide containing the cell attachment-promoting sequence, arginine-glycine-aspartic acid, yielded two polypeptide components having apparent molecular masses of approximately 160 kD reduced and 175 and 150 kD nonreduced. Immunoprecipitations from surface-iodinated WR16.1 cells or fibronectin-adherent thymocytes using a rabbit antiserum raised against the fibronectin receptor that is present on human fibroblasts revealed, in each case, the same two radiolabeled components. In contrast, immunoprecipitation from fibronectin-nonadherent T lymphoma cells, designated WR2.3, revealed the presence of only the smaller subunit. Although the lymphocyte receptor and the fibronectin receptor identified on fibroblasts share immunologic determinants, they differ in that the molecular mass of the lymphocyte protein is larger. Moreover, trypsinization of either thymocytes or the WR16.1 T lymphoma cells resulted in a subsequent loss of their ability to adhere to fibronectin-coated substrates and a reduction in the electrophoretic mobility of each of the polypeptide chains of the fibronectin receptor present on their surfaces. These changes, however, were not observed with normal rat kidney fibroblasts or mouse 3T3 fibroblasts in response to trypsinization. The data establish the existence on normal lymphocytes of fibronectin receptors that are quite similar to those found on fibroblasts. The possible function of this molecule on thymocytes is discussed.
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Dailey, M. O., J. Schreurs, and H. Schulman. "Hormone receptors on cloned T lymphocytes. Increased responsiveness to histamine, prostaglandins, and beta-adrenergic agents as a late stage event in T cell activation." Journal of Immunology 140, no. 9 (May 1, 1988): 2931–36. http://dx.doi.org/10.4049/jimmunol.140.9.2931.
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Abstract Lymphocytes have surface receptors for a variety of hormones that play an important part in modulating the immune response. Most previous studies, however, have examined the effects of hormone agonists on heterogeneous bulk populations of cells, making it difficult to precisely identify the responding target cells. We have therefore studied a set of well characterized T cell clones for a series of adenylate cyclase-linked hormone receptors and examined changes in receptor expression that occur after cell activation. All clones tested had receptors for histamine, isoproterenol, and PGE1, but not for several other cAMP-active hormone agonists. The apparent receptor affinities and their specificities were characteristic of typical histamine H2, beta 2-adrenergic, and PGE receptors. The cAMP response to PG was higher and longer lasting than that to histamine or isoproterenol, both of which appear to undergo receptor desensitization. After activation of quiescent cells in IL-2-containing media, the cAMP response to all three ligands increased, peaking 4 to 5 days after stimulation, and then returned to basal levels as the cells ceased proliferating. Inasmuch as this effect did not require Ag, it appears that the coordinate regulation of responsiveness to these ligands is a direct result of lymphocyte activation. This increase in hormone receptor activity is functionally analogous to the up-regulation of receptors for other ligands that occurs after lymphocyte activation and further demonstrates the important immunoregulatory role played by the changing repertoire of surface receptors that is associated with activation.
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Rosenberg, Kenneth M., and Nevil J. Singh. "Subset-specific neurotransmitter receptor expression tunes T cell activation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 47.22. http://dx.doi.org/10.4049/jimmunol.200.supp.47.22.
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Abstract T cells continually patrol and invade other tissues and are exposed to varying tissue-specific cues. Different tissues are typically innervated by neurons using characteristic neurotransmitters. Therefore, encounter with particular neurotransmitters has the potential to influence the tissue-specific behavior of T cells. Although neurons utilize a complex array of over 180 neurotransmitter receptor (NR) genes, we find that murine T cells in total express only a limited set (26 detected) of them. Furthermore, the expression is T cell subset-specific suggesting distinct functional roles. Several receptors, including Adrb2, Gabrr2, and Chrnb2, are most highly expressed in naïve CD4 T cells while CD8 T cells specifically express the glutamate receptor Gria3 and have high expression of the cannabinoid receptor Cnr2. Within the CD4 population, memory T cells upregulate Hrh4 and P2ry1 while the VIP receptor Vipr1 is uniquely absent from regulatory T cells. In order to understand how these distinct patterns affect immune responses, we are analyzing the functional impact of signaling T cells through them. Importantly, NR signaling pathways considerably overlap with T cell receptor (TCR) signaling pathways. Accordingly, preliminary data shows that a competing signal from NR receptors such as the β2 adrenergic, histamine H2, and VPAC1 (VIP) receptors dampens direct T cell activation through the CD3 complex. Determining how T cells integrate the complex contextual information they encounter in vivo guides our understanding of T cell decision making and will allow for the development of more targeted therapeutics.
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Robson MacDonald, H., Rosemary K. Lees, and Werner Held. "Developmentally Regulated Extinction of Ly-49 Receptor Expression Permits Maturation and Selection of NK1.1+ T Cells." Journal of Experimental Medicine 187, no. 12 (June 15, 1998): 2109–14. http://dx.doi.org/10.1084/jem.187.12.2109.
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Clonally distributed inhibitory receptors negatively regulate natural killer (NK) cell function via specific interactions with allelic forms of major histocompatibility complex (MHC) class I molecules. In the mouse, the Ly-49 family of inhibitory receptors is found not only on NK cells but also on a minor (NK1.1+) T cell subset. Using Ly-49 transgenic mice, we show here that the development of NK1.1+ T cells, in contrast to NK or conventional T cells, is impaired when their Ly-49 receptors engage self-MHC class I molecules. Impaired NK1.1+ T cell development in transgenic mice is associated with a failure to select the appropriate CD1-reactive T cell receptor repertoire. In normal mice, NK1.1+ T cell maturation is accompanied by extinction of Ly-49 receptor expression. Collectively, our data imply that developmentally regulated extinction of inhibitory MHC-specific receptors is required for normal NK1.1+ T cell maturation and selection.
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Osborne, Douglas, and Daniel Billadeau. "Role of SNX17 in receptor recycling and antigen recognition by T cells. (IRC2P.445)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 58.2. http://dx.doi.org/10.4049/jimmunol.192.supp.58.2.
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Abstract A key component in T cell activation is the endosomal recycling of receptors to the cell surface allowing for continual integration of signaling and antigen recognition. Multiple early endosomal associated proteins have been found to interact with T cell surface receptors and play a role in the recycling and transport of these receptors to the cell surface. One endosomal protein possibly involved in T cell receptor transport is sorting nexin 17 (SNX17). SNX17 has been found to bind with receptors involved in T cell activation, but its role in receptor recycling and T cell activation is unknown. Using lentivirus shRNA against SNX17, we have found that the knockdown of the SNX17 protein resulted in fewer T-APC conjugates, lower CD69, TCR, and LFA-1 surface expression, as well as lower overall TCR recycling compared to control T cells. Using immunofluorescence, we have found that SNX17 colocalizes with TCR and localizes to the peripheral-SMAC at the immune synapse in T-APC conjugates. This data suggest that SNX17 plays a synergistic role in the maintenance of normal surface levels of activating receptors and integrins to permit optimum T cell activation at the immune synapse.
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Fortune, F., J. Freysdottir, and J. Walker. "T cells expressing γδ receptors and Fcα receptors in Behcet's disease." Immunology Letters 56 (May 1997): 308. http://dx.doi.org/10.1016/s0165-2478(97)86241-4.
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Bebes, Attila, Ferenc Kovács-Sólyom, Judit Prihoda, Róbert Kui, Lajos Kemény, and Rolland Gyulai. "Interleukin-1 Receptors Are Differentially Expressed in Normal and Psoriatic T Cells." Mediators of Inflammation 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/472625.
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This study was carried out to examine the possible role of interleukin-1 (IL-1) in the functional insufficiency of regulatory T cells in psoriasis, by comparing the expression of IL-1 receptors on healthy control and psoriatic T cells. Patients with moderate-to-severe chronic plaque psoriasis and healthy volunteers, matched in age and sex, were selected for all experiments. CD4+CD25−effector and CD4+CD25+CD127lowregulatory T cells were separated and used for the experiments. Expression of the mRNA of IL-1 receptors (IL-1R1, IL-1R2, and sIL-1R2) was determined by quantitative real-time RT-PCR. Cell surface IL-1 receptor expression was assessed by flow cytometry. Relative expression of the signal transmitting IL-1 receptor type 1 (IL-1R1) mRNA is higher in resting psoriatic effector and regulatory T cells, and activation induces higher IL-1R1 protein expression in psoriatic T cells than in healthy cells. Psoriatic regulatory and effector T cells express increased mRNA levels of the decoy IL-1 receptors (IL-1R2 and sIL-1R2) upon activation compared to healthy counterparts. Psoriatic T cells release slightly more sIL-1R2 into their surrounding than healthy T cells. In conclusion, changes in the expression of IL-1 receptors in psoriatic regulatory and effector T cells could contribute to the pathogenesis of psoriasis.
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ARMSTRONG, John M., Jiang Fan CHEN, Michael A. SCHWARZSCHILD, Sergey APASOV, Patrick T. SMITH, Charles CALDWELL, Pearl CHEN, et al. "Gene dose effect reveals no Gs-coupled A2A adenosine receptor reserve in murine T-lymphocytes: studies of cells from A2A-receptor-gene-deficient mice." Biochemical Journal 354, no. 1 (February 8, 2001): 123–30. http://dx.doi.org/10.1042/bj3540123.
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Agonist binding to extracellular A2A adenosine receptors (A2ARs) inhibits the activation of virtually all tested functions of T-cells and can induce apoptosis in thymocytes. The evaluation of levels of expression of these immunosuppressive receptors is expected to clarify whether the absence of spare A2ARs (no ‘receptor reserve’) might be one of the mechanisms of attenuation of the effects of extracellular adenosine on T-cells. A2A transcript is found in T-cells and functional receptors can be demonstrated, but the density of receptor on T-cells is too low to be detected by radioligand binding. Studies of direct radioligand binding to murine brain with the selective A2AR agonist [3H]CGS21680 (2-{4-[(2-carboxyethyl)-phenyl]ethylamino}-5′-N-ethylcarboxamidoadenosine) established that striata levels of A2AR are virtually absent from A2A knock-out mice. Mice that are heterozygous (A2AR+/-) for the A2AR express significantly decreased levels of A2AR. To test for the presence of spare receptors in T-cells we took advantage of this gene dose effect and examined whether the decrease in the number of receptors in thymocytes from A2AR+/- mice was proportionately reflected in a decrease in the functional cAMP response of T-cells to adenosine. cAMP accumulation and apoptosis induced by adenosine and by A2AR agonist are of a lower magnitude in T-cells from A2AR+/- heterozygous mice than in T-cells from A2AR+/+ littermate control mice. These results indicate that there is no A2AR reserve in murine T-cells. Strongly decreased adenosine-triggered cAMP increases were detected in thymocytes from A2AR-/- mice, suggesting that A2B adenosine receptors cannot fully compensate for the loss of A2ARs in murine T-cells. We conclude that the number of A2ARs is the limiting factor in determining the maximal cAMP response of T-lymphocytes to extracellular adenosine, thereby minimizing the immunosuppressive effects of extracellular adenosine.
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Speiser, Daniel E., Mikaël J. Pittet, Danila Valmori, Rod Dunbar, Donata Rimoldi, Danielle Liénard, H. Robson MacDonald, Jean-Charles Cerottini, Vincenzo Cerundolo, and Pedro Romero. "In Vivo Expression of Natural Killer Cell Inhibitory Receptors by Human Melanoma–Specific Cytolytic T Lymphocytes." Journal of Experimental Medicine 190, no. 6 (September 20, 1999): 775–82. http://dx.doi.org/10.1084/jem.190.6.775.
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Natural killer (NK) receptor signaling can lead to reduced cytotoxicity by NK cells and cytolytic T lymphocytes (CTLs) in vitro. Whether T cells are inhibited in vivo remains unknown, since peptide antigen–specific CD8+ T cells have so far not been found to express NK receptors in vivo. Here we demonstrate that melanoma patients may bear tumor-specific CTLs expressing NK receptors. The lysis of melanoma cells by patient-derived CTLs was inhibited by the NK receptor CD94/NKG2A. Thus, tumor-specific CTL activity may be decreased through NK receptor triggering in vivo.
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Schwab, R., M. K. Crow, C. Russo, and M. E. Weksler. "Requirements for T cell activation by OKT3 monoclonal antibody: role of modulation of T3 molecules and interleukin 1." Journal of Immunology 135, no. 3 (September 1, 1985): 1714–18. http://dx.doi.org/10.4049/jimmunol.135.3.1714.
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Abstract The requirements for activation of human peripheral blood T cells by the mitogenic monoclonal antibody OKT3 were examined. OKT3 binds to a T cell molecule, T3, associated with the T cell antigen receptor and involved in T cell activation. Activation of T cells by OKT3 requires signals provided by accessory cells and is IL 2 dependent. In the presence of accessory cells, OKT3 induces loss of T3 molecules from the cell surface, production of IL 2, expression of IL 2 receptors, and proliferation. Modulation of T3 molecules by OKT3 can be induced in the absence of accessory cells with anti-mouse IgG. These T cells, however, are not induced to express IL 2 receptors or secrete IL 2. The addition of IL 1 induces expression of IL 2 receptors, but does not induce IL 2 secretion or proliferation. Thus, peripheral blood T cells appear to have different requirements for activation compared with antigen-specific T cell clones that can be induced to produce IL 2 when stimulated with OKT3 and IL 1. Expression of IL 2 receptors does not require modulation of T3 molecules, because the binding of OKT3 to T cells in the presence of IL 1 alone is sufficient to induce IL 2 receptor expression. The results suggest that IL 2 secretion depends on cross-linking and modulation of T3 molecules, and additional, as yet undefined, accessory cell signals. The expression of IL 2 receptors and proliferation of T cells can be induced in the absence of these signals when exogenous IL 2 is provided.
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Hannum, C., P. Marrack, R. Kubo, and J. Kappler. "Thymocytes with the predicted properties of pre-T cells." Journal of Experimental Medicine 166, no. 4 (October 1, 1987): 874–89. http://dx.doi.org/10.1084/jem.166.4.874.
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T cell receptor synthesis in thymocytes was examined by the differential immunoprecipitation of receptors from the surfaces and interiors of metabolically labeled newborn and adult thymocytes. Precipitated molecules were then analyzed for size, charge, and state of glycosylation. Our experiments identified cells within the thymic cortex that contained a large pool of cytoplasmic-free receptor beta chain. The beta chain in this pool was synthesized and degraded rapidly and bore only high-mannose N-linked oligosaccharides. This pool was found predominantly in cells that lacked surface alpha/beta receptors and appeared in ontogeny before cells expressing surface alpha/beta. These results are consistent with a model in which the progenitor of cells with surface alpha/beta expression is the T cell equivalent of the pre-B cell, which has rearranged and expressed beta chain, but not alpha chain.
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Mazerolles, Fabienne, and Frédéric Rieux-Laucat. "PD-L1 is expressed on human activated naive effector CD4+ T cells. Regulation by dendritic cells and regulatory CD4+ T cells." PLOS ONE 16, no. 11 (November 18, 2021): e0260206. http://dx.doi.org/10.1371/journal.pone.0260206.
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The T cell expression of various co-signalling receptors from the CD28 immunoglobulin superfamily (Inducible T cell co-stimulator (ICOS), Programmed cell death 1(PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte attenuator (BTLA) or from the tumour necrosis factor receptor superfamily (glucocorticoid-induced TNFR family related (GITR), 4-1BB, and CD27), is essential for T cell responses regulation. Other receptors (such as T cell immunoglobulin and mucin domain-containing protein 3, T cell immunoglobulin and T cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene 3) are also involved in this regulation. Disturbance of the balance between activating and inhibitory signals can induce autoimmunity. We have developed an in vitro assay to simultaneously assess the function of naive CD4+ effector T cells (TEFFs), dendritic cells (DCs) and regulatory T cells (TREGs) and the expression of co-signalling receptors. By running the assay on cells from healthy adult, we investigated the regulation of activated T cell proliferation and phenotypes. We observed that TEFFs activated by DCs mainly expressed BTLA, ICOS and PD-1, whereas activated TREGs mainly expressed TIGIT, ICOS, and CD27. Strikingly, we observed that programmed death-ligand 1 (PD-L1) was significantly expressed on both activated TEFFs and TREGs. Moreover, high PD-L1 expression on activated TEFFs was correlated with a higher index of proliferation. Lastly, and in parallel to the TREG-mediated suppression of TEFF proliferation, we observed the specific modulation of the surface expression of PD-L1 (but not other markers) on activated TEFFs. Our results suggest that the regulation of T cell proliferation is correlated with the specific expression of PD-L1 on activated TEFFs.
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Simon, Bianca, Dennis C. Harrer, Beatrice Schuler-Thurner, Gerold Schuler, and Ugur Uslu. "Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer." Cancers 11, no. 5 (May 20, 2019): 696. http://dx.doi.org/10.3390/cancers11050696.
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Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.
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Helsen, Christopher, Vivian Lau, Joanne Hammill, Kenneth Mwawasi, Danielle Hayes, Arya Afsahi, Ksenia Bezverbnaya, Craig Aarts, Galina Denisova, and Jonathan Bramson. "T Cells Engineered with T Cell Antigen Coupler (TAC) Receptors for Haematological Malignancies." Blood 132, Supplement 1 (November 29, 2018): 3267. http://dx.doi.org/10.1182/blood-2018-99-119045.
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Abstract Background: We recently described the T cell antigen coupler (TAC) technology (Helsen et. al. Nature Communications) which is a chimeric receptor that targets antigens in an MHC-independent fashion and activates T cells by co-opting the natural TCR receptor. In vitro and in vivo assessments of TAC T cells in solid tumor models have revealed that TACs mediate biological effects that are distinct from conventional chimeric antigen receptors (CARs) and offer safety advantages, including greater target selectivity and reduced off-target toxicity. Here, we present in vitro and in vivo data showing that TAC-engineered T cells directed against CD19 and BCMA demonstrate robust anti-tumor efficacy in haematological malignancies with no detectable side effects. Materials and Methods: T cells from health donors were engineered with TAC receptors directed against CD19 or BCMA using lentivirus vectors. Flow cytometry was employed to measure surface expression of TAC receptors, cytokine production and proliferation of TAC T cells following stimulation with relevant target cells. Antigen-specific toxicity was measured using a luciferase-based killing assay. Anti-tumor activity was measured against acute lymphoblast leukemia for CD19 and multiple myeloma for BCMA xenografts in immunodeficient NRG mice. Results: Engineering T cells with TAC receptors targeted against either CD19 or BCMA revealed antigen-specific activation of cytokine production, cytotoxic function and proliferation. TAC T cells, but not CAR engineered T cells, show significant selectivity towards the context of antigen presentation. This is reflected by the differential proliferative response to a diverse framework of antigen surface arrangement, potentially indicating that TAC T cells are less susceptible to off target activation and the resulting toxicities. Treatment of established NALM-6 xenografts (acute lymphoblastic leukemia) and KMS-11 xenografts (multiple myeloma) with CD19 TAC T cells and BCMA TAC T cells, respectively, resulted in clearance of tumors within a few weeks of T cell infusion. Mice that cleared tumors following TAC T cell treatment were resistant to subsequent challenge with fresh tumor cells demonstrating persistence of TAC T cells. Treatment with control TAC T cells that carry no binding domain had no impact on tumor growth. Monitoring of TAC T cells post-infusion revealed robust expansion that peaked in the peripheral blood 1-2 weeks post-infusion. A clinical manufacturing protocol has been developed for the CD19 TAC T cells in anticipation of human trials. Conclusion: Our pre-clinical evaluation suggests that TAC therapy has the potential to becoming a safer and more effective alternative to conventional CAR therapy. A first in human Phase I/II trial with CD19 TAC T cells is expected to start in the first half of 2019. Disclosures Helsen: Triumvira Immunologics: Employment, Patents & Royalties. Hammill:Triumvira Immunologics: Other: Holding shares, Patents & Royalties. Mwawasi:Triumvira Immunologics: Other: Holding shares, Patents & Royalties. Hayes:Triumvira Immunologics: Employment. Afsahi:Triumvira Immunologics: Patents & Royalties. Denisova:Triumvira Immunologics: Patents & Royalties. Bramson:Triumvira Immunologics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
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Smith, Tracey J., and John H. Weis. "Mucosal T cells and mast cells share common adhesion receptors." Immunology Today 17, no. 2 (February 1996): 60–63. http://dx.doi.org/10.1016/0167-5699(96)80580-9.
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Biffen, M., and D. R. Alexander. "Mobilization of intracellular Ca2+ by adenine nucleotides in human T-leukaemia cells: evidence for ADP-specific and P2y-purinergic receptors." Biochemical Journal 304, no. 3 (December 15, 1994): 769–74. http://dx.doi.org/10.1042/bj3040769.
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The expression of purinergic receptors on human T-cells was investigated and the receptors were shown to be functionally coupled to intracellular signals in two out of eight T-leukaemia cell-lines. Addition of adenine nucleotides resulted in mobilization of intracellular Ca2+ in HPB-ALL cells and a cell line (CB1) recently isolated from a patient with T-acute lymphoblastic leukaemia. Of a range of nucleotides tested only ADP and ATP elevated intracellular levels of Ca2+, with ADP being the more potent agonist. Ca2+ mobilization by ATP was accompanied by increased inositol phosphate production and was blocked by the purinergic receptor antagonist, Reactive Blue 2, indicating that ATP was interacting with a P2y receptor. Intracellular Ca2+ release triggered by ADP was independent of both inositol phosphate production and protein tyrosine phosphorylation. Expression of the transmembrane phosphotyrosine phosphatase, CD45, had no effect on ADP-stimulated Ca2+ mobilization. Our results show that functional P2y receptors can be expressed on T-cells, and also identify a novel T-cell ADP receptor. Signals mediated by these purinergic receptors could play important roles in modulating T-cell function.
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Weiss, A., P. F. Dazin, R. Shields, S. M. Fu, and L. L. Lanier. "Functional competency of T cell antigen receptors in human thymus." Journal of Immunology 139, no. 10 (November 15, 1987): 3245–50. http://dx.doi.org/10.4049/jimmunol.139.10.3245.
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Abstract The T cell antigen receptor is likely to play a role in both positive and negative selection in the thymus. Three populations of thymocytes can be distinguished by the level of expression of the CD3-alpha/beta-chain heterodimer of the T cell antigen receptor (CD3/Ti alpha/beta) complex. Cells which fail to express these receptors or express low levels of receptors are contained in a population of thymocytes which express low levels of the CD5 antigen and are predominantly CD4+/CD8+. Thus, these cells appear to be relatively immature phenotypically. In contrast, the cells which express high levels of CD3/Ti alpha/beta co-express high levels of CD5 and are predominantly contained in the more mature single positive cells which express either CD4 or CD8. With the calcium-sensitive dye, Indo-1, and immunofluorescence, we demonstrated that, despite the relative phenotypic immaturity of cells which express low levels of CD3/Ti alpha/beta, these antigen receptors are able to mediate transmembrane signaling when stimulated with CD3 monoclonal antibodies. Although increases in calcium were observed in these CD3/Ti alpha/beta-low expressing cells in response to anti-CD3, no proliferative response was observed, even in the presence of phorbol myristate acetate. Proliferative responses were observed in the more mature cells which express high levels of CD3/Ti alpha/beta. These results suggest that, rather than a defect in the functional capability of the antigen receptor complex to mediate transmembrane signaling events, cellular responses to signals generated by the antigen receptor may differ at various stages of thymocyte development.
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Peeters, Marlies J. W., Anne Rahbech, and Per thor Straten. "TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting." Cancer Immunology, Immunotherapy 69, no. 2 (October 29, 2019): 237–44. http://dx.doi.org/10.1007/s00262-019-02421-w.
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Abstract The TAM receptors—TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocytosis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic and immune-inhibitory traits, TAM receptors have emerged as promising targets for cancer therapy. Recently, TAM receptors have been described to function as costimulatory molecules on human T cells. TAM receptors’ ambivalent functions on many different cell types therefore make therapeutic targeting not straight-forward. In this review we summarize our current knowledge of the function of TAM receptors in the tumor microenvironment. We place particular focus on TAM receptors and the recently unraveled role of MERTK in activated T cells and potential consequences for anti-tumor immunity.
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Shanker, Anil, Maria Teresa Prudente de Aquino, Thomas W. Hodo, and Roman Uzhachenko. "Glutamate receptor signaling is critical for T cell function and antitumor activity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 241.42. http://dx.doi.org/10.4049/jimmunol.204.supp.241.42.
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Abstract The interaction between the nervous system and immune system has sparked interest in recent years. Emerging evidence shows an intricate neuroimmune network. We were intrigued by the expression of various neurotransmitter receptors on T lymphocytes. Specifically, following TCR stimulation, glutamate receptors (GluR) were significantly upregulated on both CD4+ and CD8+ T cells, with a peak at 48 h. Concomitant with the upregulation of activation molecules CD69, CD25 and CD44, proliferating CD8+ T cells presented higher levels of GluA3 and mGluR1 when compared with resting cells. By blocking group I metabotropic glutamate receptors and AMPA receptors through antagonists, we show that CD8+ T cells have a delayed activation but their viability is not altered. However, GluR blockade affected CD8+ T cell proliferation and their ability to kill tumor cells in vivo or target cells in vitro. While the frequency of GluR+CD8+ T cells ranges around 30% of total CD8+ T population, the effect of blocking glutamate signaling through receptor antagonists is a dominant effect and it is mediated by transient reduction in protein phosphorylation of TCR mediated pathways as well as calcium modulation. Overall, data suggest that glutamate receptors may have a stimulatory effect on T cell activation and glutamate agonists may boost T cell response in an immunosuppressive setting such as cancer.
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Chen, Yuehong, Jianhong Sun, Huan Liu, Geng Yin, and Qibing Xie. "Immunotherapy Deriving from CAR-T Cell Treatment in Autoimmune Diseases." Journal of Immunology Research 2019 (December 31, 2019): 1–9. http://dx.doi.org/10.1155/2019/5727516.
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Chimeric antigen receptor T (CAR-T) cells are T cells engineered to express specific synthetic antigen receptors that can recognize antigens expressed by tumor cells, which after the binding of these antigens to the receptors are eliminated, and have been adopted to treat several kinds of malignancies. Autoimmune diseases (AIDs), a class of chronic disease conditions, can be broadly separated into autoantibody-mediated and T cell-mediated diseases. Treatments for AIDs are focused on restoring immune tolerance. However, current treatments have little effect on immune tolerance inverse; even the molecular target biologics like anti-TNFα inhibitors can only mildly restore immune balance. By using the idea of CAR-T cell treatment in tumors, CAR-T cell-derived immunotherapies, chimeric autoantibody receptor T (CAAR-T) cells, and CAR regulatory T (CAR-T) cells bring new hope of treatment choice for AIDs.
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Batorov, E. V., V. A. Aristova, G. Yu Ushakova, S. A. Sizikova, V. V. Denisova, E. Ya Shevela, A. A. Ostanin, and E. R. Chernykh. "Common Ɣ-chain cytokine receptors as functional phenotype markers of PD-1and TIM-3-positive T cells in multiple myeloma." Siberian journal of oncology 22, no. 1 (February 22, 2023): 43–54. http://dx.doi.org/10.21294/1814-4861-2023-22-1-43-54.
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T cells expressing checkpoint receptors PD-1, TIM-3 etc., are potential targets for monoclonal antibody immunotherapy in multiple myeloma (MM). However, checkpoint expressing T cell compartment includes different subsets, and their dysregulation following anti-checkpoint therapy can lead to the development of adverse events.The aim of this study was to evaluate activation markers – homeostatic cytokine receptors and transcription factors expressed by PD-1and TIM-3-positive T cells.Material and Methods. Relative counts of circulating PD-1and/or TIM-3-positive and negative T cells expressing common ɣ-chain cytokine receptors CD25, CD122, CD127, phosphorylated STAT5, and transcription factor EOMES associated with T cell exhaustion were studied using flow cytometry in 17 healthy donors, 22 MM patients with remission and 7 MM patients with progressive disease.Results. T cells expressing PD-1 and/or TIM-3 inhibitory checkpoint receptors in MM patients consisted of CD25+EOMESactivated cells, CD4+CD25+CD127-FOXP3+ regulatory T cells (Treg), CD4+CD25-EOMES+ dysfunctional cells. CD25+ T cells from healthy donors and MM patients, regardless of the expression of the studied checkpoint receptors, were EOMES-negative. No such association was found for CD122 and CD127 cytokine receptors. EOMES is a marker of T cell exhaustion for CD4+ T cells, but not for CD8+ T cells, in which it is more associated with activation. The proportion of CD4+ Tregs among circulating PD-1+ and TIM-3+ T cells was relatively low. A higher content of cytokine receptors in the population of TIM-3+ T cells may indicate the predominant involvement of TIM-3 in the control of homeostatic proliferation of mature T cells under lymphopenic conditions, while the expression of PD-1 may be more associated with the regulation of activation through T cell receptor. PD-1+ and/or TIM-3+ levels of activated, dysfunctional, and regulatory T cells can potentially be used to predict the safety and efficacy of targeted immunotherapy.
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Zhou, Maggie, and Henrique Borges da Silva. "Tumor-induced, TCR-independent upregulation of A2AR expression in effector CD8+ T cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 121.05. http://dx.doi.org/10.4049/jimmunol.208.supp.121.05.
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Abstract The tumor microenvironment (TME) is characterized by high levels of extracellular ATP (eATP) and adenosine, which are sensed by purinergic receptors. CD8+ T cells express two important receptors that bind these ligands: the extracellular receptor P2RX7 binds eATP and is generally immunostimulatory, while the adenosine receptor A2AR promotes immunosuppression. However, the role of the TME itself in the T cell expression of purinergic receptors is not clear. We used in vitro co-cultures of tumor cells and CD8+ T cells, and specifically found that A2AR is significantly upregulated after activation, in a tumor cell number-correlated manner. These tumor-induced changes in A2AR expression are independent of TCR:MHC contact, which was evidenced by co-cultures using transwells to physically separate tumor cells and T cells, as well as distinct combination of transgenic T cells and tumors. In vivo murine solid tumor models confirmed that tumor-infiltrating CD8+ T cells upregulate A2AR. As previously found by our group, P2RX7 expression is limited to a small percentage of tumor-infiltrating CD8+ T cells. Interestingly, we identified that these few P2RX7-expressing tumor-infiltrating CD8+ T cells are enriched for high A2AR expression – suggesting that co-expression of these two receptors is favored in T cells exposed to tumors. Overall, our findings suggest that TME exposure – likely through TCR-independent factors – directly promote the expression of A2AR in CD8+ T cells. We are currently investigating the nature of the tumor-derived factor(s) promoting this upregulation, as well as the possible role of A2AR/P2RX7 co-expressing tumor-infiltrating CD8+ T cells as effector antitumor cells with longer intratumoral lifespan. Supported by grants from NIH (R00 AI139381, NIAID).
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Jung, T. M., W. M. Gallatin, I. L. Weissman, and M. O. Dailey. "Down-regulation of homing receptors after T cell activation." Journal of Immunology 141, no. 12 (December 15, 1988): 4110–17. http://dx.doi.org/10.4049/jimmunol.141.12.4110.
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Abstract The specific pattern of lymphocyte localization and recirculation is important for the induction and expression of normal immune responses. In order to home to lymph nodes (LN), lymphocytes must first recognize and bind to specific high endothelial venules (HEV) in the LN. Binding to LN HEV is mediated by specific lymphocyte receptors, termed homing receptors, which are recognized by the mAb MEL-14. We examined the changes that occur in homing receptor expression after activation of murine T lymphocytes in vitro. Cells activated in MLC or by Con A undergo a 75% loss in their ability to recognize HEV, as demonstrated by a decrease in binding to HEV in vitro. Large, activated cells isolated from a primary MLC by elutriator centrifugation were completely unable to recognize HEV, whereas the small cells in the same culture continued to bind well. Flow cytometric analysis with MEL-14 showed that the activated fraction had lost expression of gp90MEL-14, the homing receptor Ag, whereas the inactivated cells remained MEL-14+. Concomitant with the loss of homing receptor expression, most of the activated cells became strongly peanut agglutinin (PNA)-positive, demonstrating a marked change in surface glycosylation. Thus, these MLC consist of two major populations of T cells--small, inactivated lymphocytes that are MEL-14+PNAlo and large, activated blast cells that are MEL-14-PNAhi. Purified MEL-14+ T cells activated by Con A gave rise to MEL-14- progeny, showing that gp90MEL-14 is lost from gp90MEL-14-positive precursors, rather than from the selective growth of MEL-14- cells. Furthermore, the loss of Ag expression on at least some activated cells is reversible in resting culture, with almost half of the cells reverting to MEL-14+ after the cessation of stimulation. These experiments show that activation of T cells results in down-regulation of surface homing receptors, resulting in their inability to recognize and bind to the endothelial surface of HEV. This suggests that the activation of T cells in vivo would result in a dramatic and physiologically significant change in their migration and localization properties which would be important during a normal immune response.