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1
Ravel, Jean-Marie, and Emmanuel J. M. Mignot. "Narcolepsie : une maladie auto-immune affectant un peptide de l’éveil liée à un mimétisme moléculaire avec des épitopes du virus de la grippe." Biologie Aujourd’hui 213, no. 3-4 (2019): 87–108. http://dx.doi.org/10.1051/jbio/2019026.
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La narcolepsie et la cataplexie sont décrites pour la première fois à la fin du XIXe siècle en Allemagne et en France. La prévalence de la maladie est établie à 0,05 % et un modèle canin est découvert dans les années 1970. En 1983, une étude japonaise révèle que les patients narcoleptiques sont porteurs d’un marqueur génétique unique, l’antigène leucocytaire HLA-DR2, suggérant l’auto-immunité comme cause de la maladie. Il faudra attendre 1992 pour qu’il soit montré, grâce à une étude chez des patients afro-américains, que DQ0602, un autre gène HLA, est la véritable cause de cette association. Des études pharmacologiques conduites sur le modèle canin établissent que la stimulation dopaminergique est le mode d’action des stimulants sur l’éveil, tandis que les antidépresseurs suppriment la cataplexie en inhibant la recapture adrénergique. Aucune association HLA n’est cependant mise en évidence chez les chiens, suggérant une cause distincte de la maladie humaine. Une étude de liaison génétique chez les chiens, initiée en 1988, révèle en 1999 que la narcolepsie canine est causée par des mutations du récepteur 2 de l’hypocrétine (orexine). En 2000, l’hypocrétine-1/orexine A est mesurée dans le liquide céphalo-rachidien (LCR) et on découvre qu’elle est indétectable chez la plupart des patients narcoleptiques, établissant qu’un déficit hypocrétinergique est la cause de la narcolepsie humaine. La diminution de l’hypocrétine-1 dans le LCR, secondaire à la perte des 70 000 neurones hypothalamiques produisant l’hypocrétine, est démontrée, ce qui, avec l’association au locus HLA, suggère qu’une destruction immunitaire de ces cellules est la cause de la maladie. D’autres études génétiques, notamment d’association à l’échelle du génome (GWAS), révèlent l’existence de nombreux facteurs génétiques prédisposant à la narcolepsie, la plupart étant également impliqués dans d’autres maladies auto-immunes. Une association forte et unique avec les loci des récepteurs lymphocytaires T (TCR) alpha et bêta est aussi observée, suggérant un rôle prépondérant des lymphocytes T. En dépit de nombreux efforts, toutes les tentatives visant à démontrer la présence d’auto-anticorps contre les cellules à hypocrétine dans la narcolepsie échouent, et la cause auto-immune présumée de cette maladie reste à l’état d’hypothèse. À la suite de la grippe pandémique influenza A pH1N1 en 2009, de nombreux cas de narcolepsie apparaissent, suggérant un mimétisme moléculaire avec le virus de la grippe qui pourrait déclencher la maladie auto-immune. Cette hypothèse est confirmée par un criblage peptidique montrant une plus grande réactivité des lymphocytes T CD4+ à un segment spécifique de l’hypocrétine (HCRTNH2) et une réactivité croisée des TCR correspondants à un segment d’hémagglutinine de pH1N1 qui partage une homologie avec HCRTNH2. De façon remarquable, le TCR le plus fréquent dans la population et qui reconnaît ces antigènes contient des séquences TRAJ24 ou TRVB4-2, segments modulés par des polymorphismes génétiques associés à la narcolepsie dans les études GWAS. Il est probable que les lymphocytes T CD4+ autoréactifs avec HCRTNH2 recrutent par la suite des lymphocytes T CD8+ qui détruisent les cellules à hypocrétine. On peut s’attendre à ce que d’autres séquences mimiques grippales inconnues soient découvertes prochainement puisque la narcolepsie existait avant 2009. Ces découvertes démontrent enfin la cause auto-immune de la narcolepsie. Les travaux menés au cours des années sur la narcolepsie offrent une perspective unique sur la conduite de la recherche sur l’étiopathogénie d’une maladie bien identifiée.
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Viret, C., and M. Chérel. "Les lymphocytes T exprimant le récepteur NK1.1." médecine/sciences 12, no. 11 (1996): 1241. http://dx.doi.org/10.4267/10608/657.
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Takayama, H., and M. V. Sitkovsky. "Antigen receptor-regulated exocytosis in cytotoxic T lymphocytes." Journal of Experimental Medicine 166, no. 3 (September 1, 1987): 725–43. http://dx.doi.org/10.1084/jem.166.3.725.
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We demonstrate here that T cell receptor for antigen (TCR)-triggered exocytosis in cytotoxic T lymphocytes (CTL) is not constitutive and is regulated through crosslinking of the TCR by antigen or monoclonal anti-TCR antibodies. Morphological and biochemical data using three different biochemical markers of granules and Percoll gradient fractionation analysis are presented, suggesting that TCR-triggered exocytosis is accompanied by the loss of granules from CTL and appearance of intragranular proteins and enzymatic activities in the incubation medium. The strict requirement for crosslinking of the TCR in exocytosis triggering could be bypassed by protein kinase C activators (phorbol esters or bryostatin I and II) acting in synergy with Ca2+ ionophores. It is shown that external Ca2+ is obligatory for both the TCR-triggered and for the PMA/A23187-triggered exocytosis, since Ca2+ chelators and divalent cations that compete with Ca2+ for A23187 can inhibit exocytosis of granules. These data suggest that Ca2+ from intracellular stores is not sufficient to support exocytosis in CTL. Ca2+ channel blockers and calmodulin antagonists significantly inhibited TCR-triggered exocytosis without affecting the basal level of secretion. The described results are consistent with a model in which exocytosis of granules in CTL is triggered by the crosslinking of TCR, transmembrane protein kinase C activation, and external Ca2+ translocation through CTL plasma membrane Ca2+ channels and modulation of activity of Ca2+, calmodulin-dependent enzymes, and cytoskeletal proteins.
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Pluschke, G., D. Rüegg, R. Hohlfeld, and A. G. Engel. "Autoaggressive myocytotoxic T lymphocytes expressing an unusual gamma/delta T cell receptor." Journal of Experimental Medicine 176, no. 6 (December 1, 1992): 1785–89. http://dx.doi.org/10.1084/jem.176.6.1785.
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Polymyositis mediated by gamma/delta T cells is a unique disease in which autoaggressive T lymphocytes surround, invade, and destroy muscle fibers. Histochemically, the vast majority of muscle-infiltrating T cells in a patient with polymyositis were reactive with a pan-gamma/delta T cell receptor (TCR)-specific monoclonal antibody (TCR-delta 1+), but unlike > 90% of peripheral blood gamma/delta T cells, these lymphocytes did not react with V delta 1- or V gamma 9-specific antibodies (A13- and Ti gamma A-, respectively). Differential reactivity with two different V delta 2-specific monoclonal antibodies (BB3-/TiV-delta 2+) indicated that the infiltrating T cells express a V delta 2-containing TCR with unusual additional structural features. Using conventional and anchored polymerase chain reaction for the analysis of TCR transcripts, we found a striking predominance of one unusual V delta 2-J delta 3 recombination and one V gamma 3-J gamma 1 recombination. Both the unusual phenotype (TCR-delta 1+/A13-/Ti gamma A-/BB3-/TiV-delta 2+) and the dominance of distinct TCR transcripts are compatible with the assumption that one T cell clone, which expresses a V gamma 3-J gamma 1-C gamma 2/V delta 2-J delta 3-C delta disulfide-linked TCR, dominates among the infiltrating T cells of the polymyositis muscle specimen analyzed.
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Hubert, P. "Mécanisme d'activation des lymphocytes T par le complexe CD3-récepteur T." La Revue de Médecine Interne 17, no. 11 (November 1996): 954–55. http://dx.doi.org/10.1016/0248-8663(96)88133-1.
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Malissen, M., and B. Malissen. "Réarrangements somatiques des gènes du récepteur des lymphocytes T." médecine/sciences 2, no. 6 (1986): 304. http://dx.doi.org/10.4267/10608/3511.
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Neudorfer, Julia, Daniel Sommermeyer, Christian Peschel, Thomas Blankenstein, Wolfgang Uckert, and Helga Bernhard. "Redirecting Human T Lymphocytes toward Tumor-Associated Antigens by T Cell Receptor (TCR) Replacement." Blood 108, no. 11 (November 16, 2006): 3711. http://dx.doi.org/10.1182/blood.v108.11.3711.3711.
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Abstract The gene transfer of alpha and beta chains derived from a defined TCR has been successfully applied to endow T cells with specificities directed against tumor-associated antigens. However, it is still unclear if the transfer of TCR genes into T cells that already express an endogenous TCRalpha and beta chain leads to engineered T cells expressing four different TCR complexes on their cell surface. Mixed TCR heterodimers composed of endogenous and exogenous TCR chains may acquire new specificities, which may cause unwanted reactions in patients following adoptive T cell transfer. We examined the possibility of mixed TCR heterodimer formation using defined conditions of single TCR chain transfer into human cytotoxic T cell (CTL) clones specific for CMV and Melan-A, respectively. After stimulation for three days CTLs were retrovirally transduced with the beta chain derived from a gp100-specific TCR. The expression of the exogenous (transduced) and the endogenous beta chain was distinguished by flow cytometry using antibodies against the different Vbeta motives. Indeed, CTLs that had been transduced with the single beta chain expressed this chain on the cell surface indicating the formation of mixed TCRs, because the expression of the exogenous TCRbeta chain requires the pairing with the endogenous TCRalpha chain. Furthermore, we transduced the CTL clones with both the TCRalpha and beta chain derived from a gp100-specific TCR. The transduced T cells were positively stained with an A2/gp100 multimer documenting the correct formation of the exogenous TCR chains. Functionality of transduced CTL clones was tested by antigen-specific IFN-gamma release and cytolytic activity. The TCR-transduced T cells were sorted with the A2/gp100 multimer and expanded for two weeks. Double staining with HLA multimers for the endogenous and the transduced TCRs showed the downregulation of the endogenous TCRs in three different CTL clones. In one CTL clone, the endogenous TCR was even replaced by the exogenous TCR as documented by flowcytometry and antigen-specific T cell function. In conclusion, transfer of single TCR chains in CTL clones can result in the formation of TCR heterodimers. However, our results also show that complete TCRs are predominantly expressed or can even replace other TCRs following transfer. The development of dominant TCRs will facilitate the therapeutical approaches of adoptive transfer regimens based on TCR-transduced T cells, because dominant TCRs can be selected or TCRs can be modified to be more dominant.
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Moretta, A., C. Bottino, D. Pende, G. Tripodi, A. M. Orengo, R. Millo, P. G. Pelicci, E. Ciccone, and L. Moretta. "Human T lymphocytes expressing TCR gamma/delta." Research in Immunology 141, no. 6 (January 1990): 630–35. http://dx.doi.org/10.1016/0923-2494(90)90072-7.
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Kessler, Benedikt, Denis Hudrisier, Jean-Charles Cerottini, and Immanuel F. Luescher. "Role of CD8 in Aberrant Function of Cytotoxic T Lymphocytes." Journal of Experimental Medicine 186, no. 12 (December 15, 1997): 2033–38. http://dx.doi.org/10.1084/jem.186.12.2033.
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Using H-2Kd-restricted photoprobe-specific cytotoxic T lymphocyte (CTL) clones, which permit assessment of T cell receptor (TCR)-ligand interactions by TCR photoaffinity labeling, we observed that the efficiency of antigen recognition by CTL was critically dependent on the half-life of TCR-ligand complexes. We show here that antigen recognition by CTL is essentially determined by the frequency of serial TCR engagement, except for very rapid dissociations, which resulted in aberrant TCR signaling and antagonism. Thus agonists that were efficiently recognized exhibited rapid TCR–ligand complex dissociation, and hence a high frequency of serial TCR engagement, whereas the opposite was true for weak agonists. Surprisingly, these differences were largely accounted for by the coreceptor CD8. While it was known that CD8 substantially decreases TCR–ligand complex dissociation, we observed in this study that this effect varied considerably among ligand variants, indicating that epitope modifications can alter the CD8 contribution to TCR-ligand binding, and hence the efficiency of antigen recognition by CTL.
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Tjon, Jennifer M. L., Wieke H. M. Verbeek, Yvonne M. C. Kooy-Winkelaar, Binh H. Nguyen, Arno R. van der Slik, Allan Thompson, Mirjam H. M. Heemskerk, et al. "Defective synthesis or association of T-cell receptor chains underlies loss of surface T-cell receptor–CD3 expression in enteropathy-associated T-cell lymphoma." Blood 112, no. 13 (December 15, 2008): 5103–10. http://dx.doi.org/10.1182/blood-2008-04-150748.
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Abstract Enteropathy-associated T-cell lymphoma, an often fatal complication of celiac disease, can result from expansion of aberrant intraepithelial lymphocytes in refractory celiac disease type II (RCD II). Aberrant intraepithelial lymphocytes and lymphoma cells are intracellularly CD3ϵ+ but lack expression of the T-cell receptor (TCR)–CD3 complex on the cell surface. It is unknown what causes the loss of TCR-CD3 expression. We report the isolation of a cell line from an RCD II patient with the characteristic phenotype of enteropathy-associated T-cell lymphoma. We demonstrate that in this cell line the TCR-α and -β chains as well as the CD3γ, CD3δ, CD3ϵ, and ζ-chains are present intracellularly and that assembly of the CD3γϵ, CD3δϵ, and ζζ-dimers is normal. However, dimerization of the TCR chains and proper assembly of the TCR-CD3 complex are defective. On introduction of exogenous TCR-β chains, but not of TCR-α chains, assembly and functional cell surface expression of the TCR-CD3 complex were restored. Defective synthesis of both TCR chains was found to underlie loss of TCR expression in similar cell lines isolated from 2 additional patients. (Pre)malignant transformation in RCD II thus correlates with defective synthesis or defective association of the TCR chains, resulting in loss of surface TCR-CD3 expression.
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Borst, J., J. J. van Dongen, R. L. Bolhuis, P. J. Peters, D. A. Hafler, E. de Vries, and R. J. van de Griend. "Distinct molecular forms of human T cell receptor gamma/delta detected on viable T cells by a monoclonal antibody." Journal of Experimental Medicine 167, no. 5 (May 1, 1988): 1625–44. http://dx.doi.org/10.1084/jem.167.5.1625.
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A second type of TCR molecule has been identified on human and murine T lymphocytes, which involves the protein products of the gamma and delta genes. T lymphocytes bearing this receptor may constitute a separate cell lineage with a distinct immune function. We have produced an mAb, which specifically detects human TCR-gamma/delta in native as well as denatured states, this in contrast to previously used anti-gamma chain peptide sera, which only reacted with denatured protein. The receptor occurs in different molecular forms, with or without interchain disulphide bonds, in which a delta chain may or may not be detected by cell surface iodination. The mAb is reactive with all these receptor forms. Therefore, this antibody could be used to determine the expression of TCR-gamma/delta on viable human T lymphocytes. In normal individuals, TCR-gamma/delta was found on a subset composing 2-7% of CD3+ lymphocytes in peripheral blood and 0.1-1.0% in thymus. The majority of these cells do not express the CD4 or CD8 antigens, although a significant percentage of CD8+ cells was found. TCR-gamma/delta+ cells in peripheral blood are resting lymphocytes, as judged by ultrastructural analysis. T cell clones with different receptor types can display MHC-nonrestricted cytolytic activity, which is shown to be induced by the culture conditions, most likely by growth factors such as IL-2. This strongly suggests that TCR-gamma/delta does not play a role in target cell recognition in MHC-nonrestricted cytotoxicity. The anti-TCR-gamma/delta antibody can specifically induce cytotoxic activity in clones expressing the receptor, but in addition inhibit growth factor induced cytotoxicity, which indicates a regulatory role of the TCR-gamma/delta/CD3 complex in MHC-nonrestricted cytotoxicity.
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Groh, V., S. Porcelli, M. Fabbi, L. L. Lanier, L. J. Picker, T. Anderson, R. A. Warnke, A. K. Bhan, J. L. Strominger, and M. B. Brenner. "Human lymphocytes bearing T cell receptor gamma/delta are phenotypically diverse and evenly distributed throughout the lymphoid system." Journal of Experimental Medicine 169, no. 4 (April 1, 1989): 1277–94. http://dx.doi.org/10.1084/jem.169.4.1277.
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A direct quantitative and phenotypic cytofluorographic analysis of TCR-gamma/delta+ lymphocytes as well as an immunohistologic study of their tissue distribution and microanatomy was made possible by the availability of two mAbs (anti-TCR-delta 1 and anti-C gamma M1) specific for framework determinants on human TCR gamma and delta chains, respectively. TCR-gamma/delta+ lymphocytes, ranging between greater than 0.5 and 16% of CD3+ cells, were found in fetal and postnatal thymus, fetal and adult peripheral lymphoid organs, and adult peripheral blood. While TCR-gamma/delta+ lymphocytes comprised a small subpopulation of T cells (mean, approximately 4%) occasionally greater than 10-16% of CD3+ cells expressed TCR-gamma/delta. Virtually all TCR-gamma/delta+ thymocytes/lymphocytes expressed CD7, CD2, and CD5 but were heterogeneous with respect to their expression of CD1, CD4, CD8, CD28, CD11b, CD16, and Leu-7. Human TCR-gamma/delta+ cells populate both organized lymphoid tissues (thymus, tonsil, lymphnode, and spleen) as well as the gut- and skin-associated lymphoid systems at similar frequencies without obvious tropism for epithelial microenvironments. TCR-gamma/delta+ lymphocytes tend to be located within a given organ wherever TCR-alpha/beta+ lymphocytes are found. This study shows that TCR-gamma/delta+ lymphocytes constitute a small but numerically important, phenotypically diverse T cell population distributed throughout the body. These results support the concept that TCR-gamma/delta+ cells comprise a distinct, functionally heterogeneous, mature T cell sublineage that may substantially broaden the T cell repertoire at all immunologically relevant sites.
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Miyagawa, Y., T. Matsuoka, A. Baba, T. Nakamura, T. Tsuno, A. Tamura, K. Agematsu, A. Yabuhara, Y. Uehara, and H. Kawai. "Fetal liver T cell receptor gamma/delta+ T cells as cytotoxic T lymphocytes specific for maternal alloantigens." Journal of Experimental Medicine 176, no. 1 (July 1, 1992): 1–7. http://dx.doi.org/10.1084/jem.176.1.1.
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We have established fetal liver-derived T cell receptor (TCR) gamma/delta+, CD3+ T cell lines that are cytotoxic for maternal T cells. Fetal liver-derived lymphoid progenitors yielded predominantly TCR-gamma/delta+ cell clusters when cultured on fetal bone marrow-derived stromal cells in the presence of a cytokine cocktail under magnetic force. These tightly adherent clusters were cloned by limiting dilution and the resulting cell lines analyzed for phenotype and function. Six of eight TCR-gamma/delta lines from 8-9.5-wk gestation fetuses were V delta 2+ as compared with zero of eight lines from later stages of gestation (10 and 15 wk), where all the lines were V delta 1+. In cytotoxicity assays, these TCR-gamma/delta+, CD3+, CD4-, and CD8+ or CD8- long-term cultured lymphoid cells (LLC) were killer cells active against the class I antigens on maternal T cells. Of the cell lines, the CD8+ TCR-gamma/delta+ LLC had the highest levels of killer activity. Thus fetal liver TCR-gamma/delta+ T cells may play a crucial role in protection against invading maternal T cells generated in the feto-maternal interaction.
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Willinger, Tim, Matthew Staron, Shawn M. Ferguson, Pietro De Camilli, and Richard A. Flavell. "Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes." Proceedings of the National Academy of Sciences 112, no. 14 (March 23, 2015): 4423–28. http://dx.doi.org/10.1073/pnas.1504279112.
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Prolonged T-cell receptor (TCR) signaling is required for the proliferation of T lymphocytes. Ligation of the TCR activates signaling, but also causes internalization of the TCR from the cell surface. How TCR signaling is sustained for many hours despite lower surface expression is unknown. Using genetic inhibition of endocytosis, we show here that TCR internalization promotes continued TCR signaling and T-lymphocyte proliferation. T-cell–specific deletion of dynamin 2, an essential component of endocytosis, resulted in reduced TCR signaling strength, impaired homeostatic proliferation, and the inability to undergo clonal expansion in vivo. Blocking endocytosis resulted in a failure to maintain mammalian target of rapamycin (mTOR) activity and to stably induce the transcription factor myelocytomatosis oncogene (c-Myc), which led to metabolic stress and a defect in cell growth. Our results support the concept that the TCR can continue to signal after it is internalized from the cell surface, thereby enabling sustained signaling and cell proliferation.
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Brocker, T., and K. Karjalainen. "Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes." Journal of Experimental Medicine 181, no. 5 (May 1, 1995): 1653–59. http://dx.doi.org/10.1084/jem.181.5.1653.
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Activation studies performed with transfected T cell hybridomas and tumors revealed that chimeric molecules containing the CD3 epsilon or zeta chain intracytoplasmic portions can induce the complete effector functions normally seen only when the complete T cell receptor (TCR)/CD3 complexes of T lymphocytes are triggered. Therefore, the zeta chain, with its three antigen recognition activation motives, is thought to connect the antigen-binding Ti chains with the intracellular signaling machinery of the T cell. Here we demonstrate that the cytoplasmic portion of the TCR-zeta chain is not sufficient to activate resting T lymphocytes when cells from transgenic mice expressing a chimeric zeta receptor are used. However, after (in vivo and in vitro) activation through their endogenous TCR/CD3 complexes, the preactivated T lymphocytes could be triggered through the zeta chimera to the same extent as when they were activated through their endogenous TCR/CD3 complexes. They were able to proliferate and elicit cytotoxic functions when triggered through their zeta chimeras. These results suggest that the triggering requirements for effector functions seem to be different in resting than in activated T cells.
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Shichishima, Akiko, Hideyoshi Noji, Kazuhiko Ikeda, Yukio Maruyama, and Tsutomu Shichishima. "High Frequencies of Increased Interferon-γ-Producing and/or Skewed CD8+ T Lymphocyte Subfamilies in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)." Blood 108, no. 11 (November 16, 2006): 980. http://dx.doi.org/10.1182/blood.v108.11.980.980.
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Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematological disorder affecting all hematopoietic lineages, which lack glycosylphosphatidylinositol (GPI)-anchored membrane proteins due to somatic mutations in the phosphatidylinositol glycan-class A gene, and is one disorder of bone marrow failure (BMF) syndromes. Autoreactive T lymphocytes are implicated in some of the immune mechanisms involved in PNH. In fact, we reported recently that the HLA-DRB1*1501 allele and HLA-A*0206 allele is frequent and is related to grading of hemolysis, respectively, in PNH patients (Shichishima T et al, Blood, 2002 and Haematologica, 2006, respectively). However, some characteristics of CD4+ and CD8+ T lymphocytes, including GPI-negative CD4+ and CD8+ T lymphocytes, in PNH patients remain unknown. To know some characteristics of CD4+ and CD8+ T lymphocytes with and without expressions of GPI proteins in PNH, we examined preferential variable beta chain (Vβ) repertoires of the T-cell receptor (TCR) and expressions of interferon-γ (IFN-γ) by flow cytometry and the TCR Vβ complementarity-determining region 3 (CDR3) spectratypes by genetic methods at the same time in CD4+CD59+, CD4+CD59−, CD8+CD59+, and/or CD8+CD59− T lymphocytes from 10 Japanese patients, including 6 and 4 with the HLA-DRB1*1501 allele and HLA-A*0206 allele, respectively, and from 5 age-matched healthy individuals. In the analyses of TCR Vβ repertoires, over-expressed TCR Vβ subfamilies were found in any T lymphocytes subsets from all the patients. We found significantly higher numbers (mean ± standard deviation; 1.9 ± 1.2) of over-expressed TCR Vβ subfamilies in CD8+CD59+ T lymphocytes from PNH patients compared with those (0 ± 0, p <0.01) from healthy individuals. In the TCR Vβ CDR3 spectratyping, skewed TCR Vβ CDR3 spectatypes were found in more than one TCR Vβ subfamilies of CD3+CD4+CD59−, CD3+CD8+CD59+, and CD3+CD8+CD59− T lymphocytes from all the PNH patients. The numbers of skewed TCR Vβ CDR3 spectatypes in CD3+CD8+CD59+ (4.0 ± 3.3) and CD3+CD8+CD59− (7.5 ± 3.9) T lymphocytes from one PNH patient were significantly greater than those in CD3+CD4+CD59+ T lymphocytes (0.6 ± 1.0, p <0.005) and CD3+CD4+CD59− (2.5 ± 1.5, p <0.002), respectively. Skewed TCR Vβ CDR3 spectatypes were found commonly in Vβ 25 subfamily of CD3+CD8+CD59+ and CD3+CD8+CD59− T lymphocytes from all of 4 PNH patients with the HLA-A*0206 allele. In the analyses of IFN-γ expressions, more than one TCR Vβ subfamiliy with over-expression of IFN-γ was found in CD8+CD59+ and/or CD8+CD59− T lymphocytes from 9 patients and in CD4+CD59+ and/or CD4+CD59− T lymphocytes from 8 patients. The numbers of TCR Vβ subfamiliy with over-expression of IFN-γ in CD8+CD59+ T lymphocytes (5.2 ± 4.3), but not in the other T lymphocyte subsets, from one PNH patient were significantly greater than those from healthy individuals (0 ± 0, p <0.05). However, there were no specific Vβ subfamilies determined by any analyses, described above, in PNH. In conclusion, we found high frequencies of increased IFN-γ-producing and/or skewed CD8+ T lymphocyte subfamilies with and/or without CD59 expression in PNH patients, suggesting that these cells may contribute to the occurrence of BMF rather than negative selection of PNH clones through action of IFN-γ in PNH.
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Kahn, A. "Le deuxième récepteur des lymphocytes T prend de la consistance !" médecine/sciences 3, no. 7 (1987): 431. http://dx.doi.org/10.4267/10608/3713.
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Chabannon, C., R. Bouabdallah, S. Fürst, A. Granata, C. Saillard, N. Vey, D. Mokart, et al. "CAR-T cells : lymphocytes exprimant un récepteur chimérique à l’antigène." La Revue de Médecine Interne 40, no. 8 (August 2019): 545–52. http://dx.doi.org/10.1016/j.revmed.2018.12.002.
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Davodeau, F., M. A. Peyrat, J. Gaschet, M. M. Hallet, F. Triebel, H. Vié, D. Kabelitz, and M. Bonneville. "Surface expression of functional T cell receptor chains formed by interlocus recombination on human T lymphocytes." Journal of Experimental Medicine 180, no. 5 (November 1, 1994): 1685–91. http://dx.doi.org/10.1084/jem.180.5.1685.
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Structural diversity of lymphocyte antigen receptors (the immunoglobulin [Ig] of B cells and the alpha/beta or gamma/delta T cell receptor [TCR] of T cells) is generated through somatic rearrangements of V, D, and J gene segments. Classically, these recombination events involve gene segments from the same Ig or TCR locus. However, occurrence of "trans" rearrangements between distinct loci has also been described, although in no instances was the surface expression of the corresponding protein under normal physiological conditions demonstrated. Here we show that hybrid TCR genes generated by trans rearrangement between V gamma and (D) J beta elements are translated into functional antigen receptor chains, paired with TCR alpha chains. Like classical alpha/beta T cells, cells expressing these hybrid TCR chains express either CD4 or CD8 coreceptors and are frequently alloreactive. These results have several implications in terms of T cell repertoire selection and relationships between TCR structure and specificity. First, they suggest that TCR alloreactivity is determined by the repertoire selection processes operating during lymphocyte development rather than by structural features specific to V alpha V beta regions. Second, they suggest the existence of close structural relationships between gamma/delta and alpha/beta TCR and more particularly, between V gamma and V beta regions. Finally, since a significant fraction of PBL (at least 1/10(4)) expressed hybrid TCR chains on their surface, these observations indicate that trans rearrangements significantly contribute to the combinatorial diversification of the peripheral immune repertoire.
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Davodeau, F., M. A. Peyrat, F. Romagné, A. Necker, M. M. Hallet, H. Vié, and M. Bonneville. "Dual T cell receptor beta chain expression on human T lymphocytes." Journal of Experimental Medicine 181, no. 4 (April 1, 1995): 1391–98. http://dx.doi.org/10.1084/jem.181.4.1391.
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Allelic exclusion of lymphocyte antigen receptor chains has been hypothesized as a mechanism developed by the immune system to ensure efficient lymphocyte repertoire selection and tight control of lymphocyte specificity. It was effectively shown to be operative for both the immunoglobulin (Ig) and the T cell receptor (TCR) beta chain genes. Our present observations suggest that close to 1% of human T lymphocytes escape this allelic control, and express two surface TCR beta chains with distinct superantigenic reactivities. Since this high frequency of dual beta chain expressors did not result in any dramatic immune dysregulations, these results question the need for a mechanism ensuring clonal monospecificity through allelic exclusion.
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Combadière, Behazine, Caetano Reis e Sousa, Ronald N. Germain, and Michael J. Lenardo. "Selective Induction of Apoptosis in Mature T Lymphocytes by Variant T Cell Receptor Ligands." Journal of Experimental Medicine 187, no. 3 (February 2, 1998): 349–55. http://dx.doi.org/10.1084/jem.187.3.349.
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Activation, anergy, and apoptosis are all possible outcomes of T cell receptor (TCR) engagement. The first leads to proliferation and effector function, whereas the others can lead to partial or complete immunological tolerance. Structural variants of immunizing peptide–major histocompatibility complex molecule ligands that induce selective lymphokine secretion or anergy in mature T cells in association with altered intracellular signaling events have been described. Here we describe altered ligands for mature mouse CD4+ T helper 1 cells that lead to T cell apoptosis by the selective expression of Fas ligand (FasL) and tumor necrosis factor (TNF) without concomitant IL-2, IL-3, or interferon γ production. All ligands that stimulated cell death were found to induce FasL and TNF mRNA expression and TCR aggregation (“capping”) at the cell surface, but did not elicit a common pattern of tyrosine phosphorylation of the TCR-associated signal transduction chains. Thus, TCR ligands that uniquely trigger T cell apoptosis without inducing cytokines that are normally associated with activation can be identified.
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Goodman, T., and L. Lefrancois. "Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function." Journal of Experimental Medicine 170, no. 5 (November 1, 1989): 1569–81. http://dx.doi.org/10.1084/jem.170.5.1569.
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The function and structure of the TCR proteins of intraepithelial lymphocytes (IEL) were examined using a panel of mAbs specific for TCR-gamma/delta. Three subsets of TCR-gamma/delta+ IEL could be detected with five mAbs, termed GL1-GL5. The mAbs were able to trigger lysis via crosslinking of the IEL TCR and all of the subsets were constitutively cytolytic. Immunoprecipitation of IEL TCR proteins revealed that the GL2 mAb reacted only with gamma, delta heterodimers containing high Mr delta chains, while the other mAbs precipitated all of the observed gamma and delta proteins. Two-color fluorescence analysis showed that the GL2+ subset was contained within the larger GL1+ subset. The GL3 and GL4 mAbs appear to be specific for all TCR-gamma/delta while GL2 was V delta 4 specific. Analysis of IEL for TCR-alpha/beta expression demonstrated that approximately 20% of B6 IEL were TCR-alpha/beta+. Interestingly, this population of IEL contained Thy-1- and CT1+ cells, indicating that the unique phenotype of IEL was not restricted to TCR-gamma/delta+ cells. Moreover, the TCR-alpha/beta+ IEL were also constitutively cytolytic, suggesting that the intestinal milieu was controlling the functional programming of IEL regardless of TCR type. The mAbs reported here as well as the ability to exploit the distinct phenotype of IEL should prove useful in determining the function of IEL and the TCR-gamma/delta.
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Pan, Xiaoyu, Jochen M. Rudolph, Libin Abraham, Anja Habermann, Claudia Haller, Jacomine Krijnse-Locker, and Oliver T. Fackler. "HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network–associated Lck signaling." Blood 119, no. 3 (January 19, 2012): 786–97. http://dx.doi.org/10.1182/blood-2011-08-373209.
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Abstract The Nef protein of HIV-1 facilitates viral replication and disease progression in vivo. Nef disturbs the organization of immunological synapses between infected CD4+ T lymphocytes and antigen-presenting B-lymphocytes to interfere with TCR proximal signaling. Paradoxically, Nef enhances distal TCR signaling in infected CD4+ T lymphocytes, an effect thought to be involved in its role in AIDS pathogenesis. Using quantitative confocal microscopy and cell fractionation of Nef-expressing cells and HIV-1–infected primary human T lymphocytes, we found that Nef induces intracellular compartmentalization of TCR signaling to adjust TCR responses to antigenic stimulation. Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi network (TGN), thereby preventing the recruitment of active Lck to the immunological synapse after TCR engagement and limiting signal initiation at the PM. Instead, Nef triggers Lck-dependent activation of TGN-associated Ras-Erk signaling to promote the production of the T lymphocyte survival factor IL-2 and to enhance virus spread. Overexpression of the Lck PM transporter Unc119 restores Nef-induced subversions of Lck trafficking and TCR signaling. Nef therefore hijacks Lck sorting to selectively activate TGN-associated arms of compartmentalized TCR signaling. By tailoring T-lymphocyte responses to antigenic stimulation, Nef optimizes the environment for HIV-1 replication.
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Provasi, Elena, Pietro Genovese, Angelo Lombardo, Zulma Magnani, Pei-Qi Liu, Andreas Reik, Victoria Chu, et al. "TCR Gene Editing Results in Effective Immunotherapy of Leukemia without the Development of GvHD." Blood 118, no. 21 (November 18, 2011): 667. http://dx.doi.org/10.1182/blood.v118.21.667.667.
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Abstract Abstract 667 Transfer of high-avidity T-cell receptor (TCR) genes isolated from rare tumor-specific lymphocytes into polyclonal CD8+ T cells is an attractive strategy for targeted cancer immunotherapy. However, the successful implementation of this approach is limited by technical and safety issues, including inefficient gene transfer, unstable transgene expression, exhaustion of gene-modified cells and most importantly, the unpredictable results of mispairing between the endogenous and exogenous TCR chains. Indeed, co-expression of the endogenous and exogenous TCR in the same cell not only reduces cell-surface expression of the introduced tumor-specific TCR, but also drives the potential for these gene-modified T cells to acquire autoreactive specificities. Such TCR mispairing has been shown to result in autoreactive T cells in animal models [Bendle et al., Nat Med. 2010]. To partially overcome these limitations, we have developed a novel strategy based on zinc finger nucleases (ZFNs) that permits editing of T cell specificity at the DNA level, combining the disruption of the endogenous TCR chain genes with the transfer of a tumor-specific TCR. Two sets of ZFNs were designed targeting the constant regions of the α (TRAC-ZFN) and β (TRBC-ZFN) TCR chain genes, respectively. We transiently delivered these ZFNs into primary T lymphocytes activated with anti-CD3 and anti-CD28 antibody-conjugated beads and cultured with low doses of IL-7 and IL-15, to promote the survival and expansion of the ZFN-modified cells. ZFN delivery into activated T lymphocytes abrogated expression of the CD3/TCR complex on the cell surface (% of CD3neg cells with TRAC-ZFN: 34%±11 and with TRBC-ZFN: 30%±9). No phenotypic differences were observed in CD3pos and CD3neg lymphocytes, which displayed a similar CD4/CD8 ratio while displaying an early T-cell differentiation phenotype, as evidenced by high expression of CD62L, CD27, CD28 and IL-7Rα markers. Sorted CD3neg cells proved stable in culture (demonstrating that ZFN exposure was well tolerated), and did not respond to TCR-dependent stimulation with the mitogen PHA, as expected for cells carrying a disrupted TCR gene. CD3neg cells were efficiently transduced with a lentiviral vector encoding a tumor-specific exogenous TCR chain, resulting in the restoration of cell surface translocation of CD3, thus facilitating the selective expansion of TCR-transduced cells by polyclonal stimulation. To demonstrate the antitumor activity of these modified cells we selected an HLA-A2 restricted, codon-optimized cysteine-modified TCR specific for the Wilms' tumor antigen 1 (WT1). To achieve complete editing of T cell specificity, we established a protocol that sequentially disrupted the endogenous TCR α and β chains with high efficiency (averages: 36% and 18%), followed by lentiviral transfer of the tumor-specific TCR α and β chains (average efficiencies: 65% and 25%). This procedure resulted in a population of TCR-edited lymphocytes encoding only the tumor-specific TCR that, in the absence of competition from the endogenous receptor, was expressed at high physiological levels. Accordingly, TCR-edited lymphocytes were superior to conventional TCR-transferred cells in promoting specific recognition of WT1-expressing targets, including primary leukemias, and most importantly, were devoid of residual endogenous TCR reactivity including alloreactivity. Finally, in a humanized GvHD model, we showed that, at a variance with 100% of mice infused with unmanipulated T cells, and 80% of mice receiving TCR-transferred lymphocytes developing lethal GvHD, no GvHD was observed upon infusion of matched TCR-edited cells, despite robust T cell engraftment rates across all groups. These data demonstrate that the successful genetic re-programming of T cell specificity in primary lymphocytes results in a functionally superior target specific killing activity and thus has the potential to greatly improve the safety and therapeutic benefit of cancer immunotherapy, without triggering its potentially negative effects. (Provasi and Genovese: equal contribution). Disclosures: Liu: Sangamo Biosciences: Employment. Reik:Sangamo Biosciences: Employment. Chu:Sangamo Biosciences: Employment. Paschon:Sangamo Biosciences: Employment. Zhang:Sangamo Biosciences: Employment. Bordignon:Molmed: Employment. Holmes:Sangamo Biosciences: Employment. Gregory:Sangamo Biosciences: Employment. Bonini:Molmed: Consultancy.
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Izquierdo, M., S. J. Leevers, C. J. Marshall, and D. Cantrell. "p21ras couples the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes." Journal of Experimental Medicine 178, no. 4 (October 1, 1993): 1199–208. http://dx.doi.org/10.1084/jem.178.4.1199.
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It has previously been shown in T cells that stimulation of protein kinase C (PKC) or the T cell antigen receptor (TCR) induces the rapid accumulation of the active guanosine triphosphate-bound form of p21ras. These stimuli also induce the activation of extracellular signal-regulated kinase 2 (ERK2), a serine/threonine kinase that is rapidly activated via a kinase cascade in response to a variety of growth factors in many cell types. In this study, we show that p21ras is a component of the TCR signaling pathway that controls ERK2 activation. In the human Jurkat T cell line, transient expression of constitutively active p21ras induces ERK2 activation, measured as an increase in the ability of an ERK2-tag reporter protein to phosphorylate myelin basic protein. Thus, constitutively active p21ras bypasses the requirement for PKC activation or TCR triggering to induce ERK2 activation. In addition, activation of PKC or the TCR produces signals that cooperate with activated p21ras to stimulate ERK2. Conversely, expression of a dominant negative mutant of ras, Ha-ras N17, blocks ERK2 activation after TCR stimulation, indicating that endogenous p21ras function is necessary for the TCR-stimulated ERK2 activation. Taken together, these results demonstrate that the activation of p21ras is both necessary and sufficient to induce ERK2 activation in T cells.
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Xue, Shao-An, Liquan Gao, Daniel Hart, Roopinder Gillmore, Waseem Qasim, Adrian Thrasher, Jane Apperley, et al. "Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene–transduced human T cells." Blood 106, no. 9 (November 1, 2005): 3062–67. http://dx.doi.org/10.1182/blood-2005-01-0146.
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AbstractCytotoxic T lymphocytes (CTLs) specific for an HLA-A2–presented peptide epitope of the Wilms tumor antigen-1 (WT1) can selectively kill immature human leukemia progenitor and stem cells in vitro. In this study we have used retroviral gene transfer to introduce a WT1-specific T-cell receptor (TCR) into T lymphocytes obtained from patients with leukemia and from healthy donors. TCR-transduced T cells kill leukemia cells in vitro and display WT1-specific cytokine production. Intravenous injection of TCR-transduced T cells into nonobese diabetic–severe combined immunodeficiency (NOD/SCID) mice harboring human leukemia cells resulted in leukemia elimination, whereas transfer of control T cells transduced with an irrelevant TCR was ineffective. The data suggest that adoptive immunotherapy with WT1-TCR gene–modified patient T cells should be considered for the treatment of leukemia.
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Mastaglio, Sara, Pietro Genovese, Zulma Magnani, Elena Provasi, Angelo Lombardo, Andreas Reik, Nicoletta Cieri, et al. "TCR Gene Editing Achieved In a Single Round Of T Cell Activation Is Sufficient To Redirect T Cell Specificity and Prevent GvHD." Blood 122, no. 21 (November 15, 2013): 2898. http://dx.doi.org/10.1182/blood.v122.21.2898.2898.
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Abstract The genetic transfer of tumor-specific T cell receptors (TCRs) into mature T lymphocytes enables T cell specificity to be redirected towards cancer cells, however the transfer of novel TCRs into polyclonal T cells, while overcoming tolerance barriers, may be limited by factors intrinsic to TCR biology. Specifically, the tumor-specific a and b TCR chains are expressed in lymphocytes that already bear an endogenous TCR on their cell surfaces. Gene-modified cells thus express at least two different TCRs that compete for binding to the CD3 complex, resulting in mutual TCR dilution and reduced avidity. Furthermore, since TCRs are heterodimers, the a and b chains of the endogenous TCR have the potential to mispair with the respective α and β chains of the transgenic TCR to produce a new hybrid TCR, with unpredictable and potentially harmful specificity. This represents a major concern in TCR transfer adoptive immunotherapy, both in autologous and allogeneic settings. To permanently eliminate the expression of the endogenous TCR and the risk of mispairing, our group recently developed a TCR gene editing approach. This technique is based on the transient transfer of zinc-finger nucleases (ZFN) to induce DNA double strand breaks in the constant regions of the endogenous TCR a and/or b chain genes, leading to permanent gene disruption. Upon lentiviral transfer of a tumor-specific TCR, such fully TCR-edited T cells express only the exogenous tumor-specific TCR transgenes at high levels (Provasi, Genovese et al., Nature Medicine 2012). While the complete editing procedure (both a and b TCR chains) currently requires multiple manipulation steps, ‘single TCR editing’, based on the ZFN-mediated knock-down of a single endogenous TCR chain (a or b) followed by the introduction of the tumor-specific TCR, enables the generation of redirected T cells devoid of their natural TCR repertoire during a single round of T cell activation, improving the feasibility of the clinical translation of this approach. This might be particularly useful to reduce the risk of GvHD after allogeneic hematopoietic stem cell transplantation. We exploited a HLA-A2 restricted TCR specific for NY-ESO-1, a cancer testis antigen expressed by solid tumors and hematological malignancies, to directly compare the safety and efficacy profile of unedited TCR transferred T cells (TR), single TCR edited (SE) lymphocytes and completely TCR edited (CE) T cells. We observed that gene editing does not detectably affect the phenotype, function or proliferative potential of engineered lymphocytes. Our protocols ensured the maintenance of the early differentiated memory phenotype, with enrichment in central memory and CD45RA+/CD62L+/CD95+ memory stem T (TSCM) cells. Upon lentiviral transfer of the NY-ESO-1-specific TCR, we observed significantly higher levels of the tumor-specific TCR expression, evaluated as NY-ESO-1 specific dextramer binding, in edited versus transferred T cells (relative fluorescence intensity to untransduced cells: CE: 37; SE: 31; TR: 19). Edited T cells were more efficient than unedited-TCR transferred T cells in killing NY-ESO-1-pulsed cell lines (half maximal effective peptide concentration in a 51Cr release assay: 310, 210, 186 nM for TR, SE and CE T cells respectively) and NY-ESO-1+ myeloma cell lines naturally processing the antigen. Importantly our SE and CE T cells displayed no activity against NY-ESO-1- targets. Importantly, in NSG mice, NY-ESO-1 redirected single edited and complete edited T cells completely eliminated an NY-ESO1+ HLA-A2+, WT1- myeloma cell line, that, on the contrary, expanded in bone marrow in the presence of WT1-redirected CE T cells. Our results demonstrate that the TCR single editing approach is effective in redirecting T cell specificity as evidenced by the potent anti-tumor effect observed while potentially eliminating the risk of GvHD associated with the infusion of donor-derived lymphocytes. Moreover, the relative speed and simplicity of the TCR single editing protocol should facilitate its clinical application to patients with hematological malignancies. Disclosures: Reik: Sangamo BioSciences: Employment. Holmes:Sangamo BioSciences: Employment. Gregory:Sangamo BioSciences: Employment.
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Petrie, H. T., F. Livak, D. Burtrum, and S. Mazel. "T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production." Journal of Experimental Medicine 182, no. 1 (July 1, 1995): 121–27. http://dx.doi.org/10.1084/jem.182.1.121.
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The antigen-specific receptors of T and B lymphocytes are generated by somatic recombination between noncontiguous gene segments encoding the variable portions of these molecules. The semirandom nature of this process, while desirable for the generation of diversity, has been thought to exact a high price in terms of sterile (out-of-frame) products. Historically, the majority of T lymphocytes generated in mammals were thought to be useless, either because they generated such sterile rearrangements or because the receptors generated did not appropriately recognize self-molecules (i.e., positive and negative selection). In the studies described here, we characterize the onset of T cell receptor (TCR) alpha and beta chain gene rearrangements and quantitate their progression throughout T cell development. The results show that T cell production efficiency is enhanced through (a) rearrangement of TCR-beta chain genes early during T cell development, with selective expansion of those cells possessing in-frame rearrangements; (b) deletion of sterile rearrangements at the TCR-alpha chain locus through ordered (proximal to distal) sequential recombination; and (c) modification of nonselectable alpha/beta heterodimer specificities through generation and expression of new TCR-alpha chains. In addition, we demonstrate strict correlations between successful TCR-beta gene rearrangement, the onset of TCR-alpha gene rearrangement, rapid cell division, and programmed cell death, which together serve to maintain cell turnover and homeostasis during T cell development.
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Chikamatsu, Kazuaki, Masao Eura, Koji Nakano, Yuichi Kanzaki, Keisuke Masuyama, and Takeru Ishikawa. "T-Cell Receptor Vβ Gene Rearrangements of T Lymphocytes Infiltrating the Mucosa in Chronic Sinusitis." American Journal of Rhinology 9, no. 6 (November 1995): 347–52. http://dx.doi.org/10.2500/105065895781808784.
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Lymphocytic infiltration within the mucosa of patients with chronic sinusitis may reflect an in situ immune reaction. An analysis of the T-cell receptor (TCR) expressed by these lymphocytes may help to understand T-cell immunity in chronic sinusitis. We analyzed the TCR Vβ gene rearrangements in T cells that infiltrated the mucosa of the maxillary sinuses in 24 patients with chronic sinusitis using the reverse transcription polymerase chain reaction method. The analysis of the TCR Vβ repertoire revealed a significant limited usage (P < 0.01) of the Vβ gene families, compared with peripheral blood lymphocytes that expressed all of the gene families in all these patients. The limited gene usage of the T cells suggests that bacterial or viral infection of the sinus mucosa attracts T cells that specifically respond to the bacterial or virus-derived antigens.
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Arstila, Tuula, T. Petteri Arstila, Sébastien Calbo, Françoise Selz, Michèle Malassis-Seris, Pierre Vassalli, Philippe Kourilsky, and Delphine Guy-Grand. "Identical T Cell Clones Are Located within the Mouse Gut Epithelium and Lamina Propria and Circulate in the Thoracic Duct Lymph." Journal of Experimental Medicine 191, no. 5 (March 6, 2000): 823–34. http://dx.doi.org/10.1084/jem.191.5.823.
Full textAbstract:
Murine gut intraepithelial (IEL) T cell receptor (TCR)-α/β1 lymphocytes bearing CD8α/β or CD8α/α coreceptors have been shown previously to express different oligoclonal TCR β chain repertoires in the same mouse, in agreement with other evidence indicating that these two populations belong to different ontogenic lineages, with only CD8α/β1 IELs being fully thymus dependent. CD8α/β1, but not CD8α/α1, T lymphocytes are also present in the lamina propria. Here, we show that CD8α/β+ lymphocytes from the lamina propria and the epithelium are both oligoclonal, and that they share the same TCR-β clonotypes in the same mouse, as is also the case for CD4+ T cells. Furthermore, identical T cell clones were detected among CD8α/β1 IELs and CD8α/β1 blasts circulating into the thoracic duct (TD) lymph of the same mouse, whereas TD small lymphocytes are polyclonal. These findings must be considered in light of previous observations showing that T blasts, but not small T lymphocytes, circulating in the TD lymph have the capacity of homing into the gut epithelium and lamina propria. These combined observations have interesting implications for our understanding of the recirculation of gut thymus-dependent lymphocytes and their precursors, and of the events leading up to the selection of their restricted TCR repertoire.
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Hughes, D. P., A. Hayday, J. E. Craft, M. J. Owen, and I. N. Crispe. "T cells with gamma/delta T cell receptors (TCR) of intestinal type are preferentially expanded in TCR-alpha-deficient lpr mice." Journal of Experimental Medicine 182, no. 1 (July 1, 1995): 233–41. http://dx.doi.org/10.1084/jem.182.1.233.
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Fas-mediated apoptosis is essential for activation-induced cell death of alpha/beta T cells, but it is not clear what role, if any, it plays in regulating other components of the immune system. To study the role of Fas in gamma/delta T cell development, Fas-deficient lpr mice were bred with T cell receptor alpha gene-ablated (TCR-alpha-/-) mice to generate mice deficient in one or both genes. The TCR-alpha-/-, lpr/lpr mice had a nearly 10-fold increase in total lymph node cell (LNC) number compared with Fas-intact TCR-alpha-/- mice, because of expansion of TCR-gamma/delta+ and TCR-beta+ cells. In Fas-intact TCR-alpha-/- mice, approximately one third of the LNCs expressed TCR-gamma/delta. These were evenly divided between the CD4-, CD8-alpha+ and the CD4-, CD8- subsets, and rarely expressed the B220 epitope of CD45. In contrast, in TCR-alpha-/-, lpr/lpr mice, TCR-gamma/delta+ cells comprised half of the LNCs and were primarily CD4-, CD8-, and B220+. Moreover, Fas deficiency in TCR-alpha-/- mice caused a preferential expansion of gamma/delta T cells expressing variable region genes characteristic of intestinal intraepithelial lymphocytes. These results demonstrate a role for Fas in regulating the gamma/delta T cell contribution to peripheral lymph nodes. This mechanism may be most important in limiting the access of activated intestinal intraepithelial lymphocytes to the peripheral lymphoid system.
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Pilch, H., H. Höhn, C. Neukirch, K. Freitag, P. G. Knapstein, B. Tanner, and M. J. Maeurer. "Antigen-Driven T-Cell Selection in Patients with Cervical Cancer as Evidenced by T-Cell Receptor Analysis and Recognition of Autologous Tumor." Clinical and Vaccine Immunology 9, no. 2 (March 2002): 267–78. http://dx.doi.org/10.1128/cdli.9.2.267-278.2002.
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ABSTRACT We characterized the T-cell receptor (TCR) repertoire in freshly harvested tumor lesions, in short-term-expanded CD4+ tumor infiltrating lymphocytes (TIL) as well as in CD4+ and CD8+ peripheral blood lymphocytes (PBL) from three patients with cervical cancer. Skewing of the T-cell repertoire as defined by measuring the length of the complementarity-determining region 3 (CDR3) of the TCR VA and VB chains was observed in CD8+ PBL, in freshly harvested tumor tissue, as well as in CD4+ TIL. Comparative analysis of the TCR repertoire revealed unique monoclonal TCR transcripts within the tumor lesion which were not present in PBL, suggesting selection of TCR clonotypes due to antigenic stimulation. TCR repertoire analysis of the short-term (7-day) CD4+ TIL lines revealed that the TCR composition is markedly different from that in CD4+ PBL or in the freshly harvested tumor tissue. Only one-third of CD4+ TIL lines showed HLA-DR-restricted recognition of autologous tumor cells as defined by cytolysis. These data provide support for the antigen-driven selection of T cells within cervical cancer lesions and suggest that analysis of the TCR repertoire may aid in obtaining an objective description of the immune response in patients with cervical cancer who are undergoing epitope-based immunotherapy.
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Provasi, Elena, Oscar Muniz Pello, Zulma Magnani, Jurgen Kuball, Angelo Lombardo, Attilio Bondanza, Philip D. Gregory, et al. "T Cell Receptor Gene Transfer into Naive and Central Memory Lymphocytes by Lentiviral Vectors for a Safe and Effective Adoptive Immune Therapy of Leukemia." Blood 112, no. 11 (November 16, 2008): 3529. http://dx.doi.org/10.1182/blood.v112.11.3529.3529.
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Abstract The potency of cellular adoptive immunotherapy against cancer has been revealed by persistent and complete clinical responses obtained with allogeneic hemopoietic cell transplantation (allo-HSCT) followed by the adoptive transfer of donor T lymphocytes and by initial clinical responses observed with the adoptive transfer of tumor specific cytotoxic T lymphocytes (CTLs) in cancer patients. Major hurdles limiting adoptive T cell therapy relate to toxicity (i.e. graft-versus-host disease-GvHD in allo-HSCT) and efficacy (i.e. difficulty in expanding rare, high-avidity tumor-specific CTLs in conditions that can preserve their function and prevent exhaustion). The transfer of the T cell receptor (TCR) from high-avidity tumor-specific CTLs to polyclonal lymphocytes may overcome these difficulties, but is still limited by low and transient transgene expression, unpredictable pairing of the exogenous and endogenous TCR chains and poor survival and expansion potential of gene-modified effector lymphocytes. To overcome these limitations, we cloned genes encoding a high-avidity TCR specific for an HLA-A2-restricted peptide from the oncogenic Wilms tumor antigen 1 (WT1126-135), in a third generation lentiviral vector under the control of a bi-directional PGK or a bi-directional EF1α promoter. To increase TCR expression and facilitate appropriate TCR pairing, we used a codon-optimized TCR, modified with point mutations to introduce cysteines into the constant regions of the α and 7β chains. Human T lymphocytes were efficiently transduced by both vectors, following activation with anti-CD3 and anti-CD28 antibody-conjugated beads (bCD3/CD28) and culture with low doses of IL-7/IL-15. However, the PGK promoter was superior to EF1α in sustaining stochiometric expression of WT1-specific TCR chains, at levels appropriate for efficient HLA-A2/WT1 pentamer binding (16%), for up to 50 days, in the absence of further T cell stimulation. Additionally, we observed that a phenotype consistent with early (naïve and central memory) T cell differentiation (CD45RA−/+CD62L+, CD28+CD27+, IL7Ra+, IL-2+ γIFN±) was preserved in TCR-modified lymphocytes generated in these culture conditions. Sorted naïve (CD45RA+/CD62L+) and central memory (CD45RA−/CD62L+) lymphocytes were efficiently transduced by TCR-LV and maintained the original T cell phenotype. Accordingly, TCR-modified lymphocytes showed excellent survival and expansion capacity, and, upon antigenic stimulation mediated high WT1-specific γIFN production and cytotoxic activity. To improve the safety of the strategy, we attempted sitespecific integration of transgenes using of the ZFN technology. Adenoviral transfer of a set of ZFN specific for the putative safe-harbor locus CCR5 coupled with integrase defective lentiviral vectors carrying the donor DNA flanked transgene, enables efficient site-specific integration in human lymphocytes resulting in stable transgene expression. Analyses of sorted gene-modified cells is currently ongoing. Site-specific integration of an optimized, leukemia-specific TCR into both naïve and central memory lymphocytes may represent an effective method for the generation of robust engineered tumor-specific CTLs.
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Renauld, JC. "L'IL9 et son récepteur, un modèle pour l'oncogenèse des lymphocytes T." médecine/sciences 11, no. 9 (1995): 1289. http://dx.doi.org/10.4267/10608/2449.
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Hudrisier, D., and JE Gairin. "La pharmacologie du récepteur des lymphocytes T et de ses ligands." médecine/sciences 12, no. 11 (1996): 1198. http://dx.doi.org/10.4267/10608/652.
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Kusunoki, Y., Y. Hirai, S. Kyoizumi, and M. Akiyama. "Evidence for in vivo clonal proliferation of unique population of blood CD4-/CD8- T cells bearing T-cell receptor alpha and beta chains in two normal men." Blood 79, no. 11 (June 1, 1992): 2965–72. http://dx.doi.org/10.1182/blood.v79.11.2965.2965.
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Abstract Rare T lymphocytes bearing CD3 surface antigen and T-cell receptor (TCR) alpha and beta chains, but lacking both CD4 and CD8 antigens, viz, TCR alpha beta+CD4–8- cells, appear at a frequency of 0.1% to 2% in peripheral blood TCR alpha beta+ cells of normal donors. Here we report two unusual cases, found among 100 healthy individuals studied, who showed an abnormally elevated frequency of these T cells, ie, 5% to 10% and 14% to 19%. Southern blot analyses of the TCR alpha beta+CD4–8- clones all showed the identical rearrangement patterns for each individual, demonstrating that these are derivatives of a single T cell. The same rearrangement patterns were also observed for the freshly isolated lymphocytes of TCR alpha beta+CD4-CD8- fraction, which excludes the possible bias in the processes of in vitro cloning. These TCR alpha beta+CD4–8- T cells were found to express other mature T-cell markers such as CD2, CD3, and CD5 antigens, as well as natural killer (NK) cell markers (CD11b, CD16, CD56, and CD57 antigens) for both individuals. Further, although lectin-dependent or redirected antibody- dependent cell-mediated cytotoxicities were observed for both freshly sorted lymphocytes of TCR alpha beta+CD4–8- fraction and in vitro established clones, NK-like activity was not detected.
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Kusunoki, Y., Y. Hirai, S. Kyoizumi, and M. Akiyama. "Evidence for in vivo clonal proliferation of unique population of blood CD4-/CD8- T cells bearing T-cell receptor alpha and beta chains in two normal men." Blood 79, no. 11 (June 1, 1992): 2965–72. http://dx.doi.org/10.1182/blood.v79.11.2965.bloodjournal79112965.
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Rare T lymphocytes bearing CD3 surface antigen and T-cell receptor (TCR) alpha and beta chains, but lacking both CD4 and CD8 antigens, viz, TCR alpha beta+CD4–8- cells, appear at a frequency of 0.1% to 2% in peripheral blood TCR alpha beta+ cells of normal donors. Here we report two unusual cases, found among 100 healthy individuals studied, who showed an abnormally elevated frequency of these T cells, ie, 5% to 10% and 14% to 19%. Southern blot analyses of the TCR alpha beta+CD4–8- clones all showed the identical rearrangement patterns for each individual, demonstrating that these are derivatives of a single T cell. The same rearrangement patterns were also observed for the freshly isolated lymphocytes of TCR alpha beta+CD4-CD8- fraction, which excludes the possible bias in the processes of in vitro cloning. These TCR alpha beta+CD4–8- T cells were found to express other mature T-cell markers such as CD2, CD3, and CD5 antigens, as well as natural killer (NK) cell markers (CD11b, CD16, CD56, and CD57 antigens) for both individuals. Further, although lectin-dependent or redirected antibody- dependent cell-mediated cytotoxicities were observed for both freshly sorted lymphocytes of TCR alpha beta+CD4–8- fraction and in vitro established clones, NK-like activity was not detected.
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Feigelson, Sara W., Valentin Grabovsky, Eugenia Manevich-Mendelson, Ronit Pasvolsky, Ziv Shulman, Vera Shinder, Eugenia Klein, Amos Etzioni, Memet Aker, and Ronen Alon. "Kindlin-3 is required for the stabilization of TCR-stimulated LFA-1:ICAM-1 bonds critical for lymphocyte arrest and spreading on dendritic cells." Blood 117, no. 26 (June 30, 2011): 7042–52. http://dx.doi.org/10.1182/blood-2010-12-322859.
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Kindlin-3 is a key lymphocyte function–associated antigen-1 (LFA-1) coactivator deleted in leukocyte adhesion deficiency-III (LAD-III). In the present study, we investigated the involvement of this adaptor in lymphocyte motility and TCR-triggered arrest on ICAM-1 or on dendritic cells (DCs). Kindlin-3–null primary T cells from a LAD-III patient migrated normally on the major lymph node chemokine CCL21 and engaged in normal TCR signaling. However, TCR activation of Kindlin-3–null T lymphocytes failed to trigger the robust LFA-1–mediated T-cell spreading on ICAM-1 and ICAM-1–expressing DCs that is observed in normal lymphocytes. Kindlin-3 was also essential for cytoskeletal anchorage of the LFA-1 heterodimer and for microclustering of LFA-1 within ventral focal dots of TCR-stimulated lymphocytes spread on ICAM-1. Surprisingly, LFA-1 on Kindlin-3–null lymphocytes migrating over CCL21 acquired normal expression of an epitope associated with the conformational activation of the key headpiece domain, β I. This activated LFA-1 was highly responsive to TCR-triggered ICAM-1–driven stop signals in normal T cells locomoting on CCL21, but not in their Kindlin-3–null T-cell counterparts. We suggest that Kindlin-3 selectively contributes to a final TCR-triggered outside-in stabilization of bonds generated between chemokine-primed LFA-1 molecules and cell-surface ICAM-1.
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Hinz, Thomas, Eckhart Weidmann, and Dieter Kabelitz. "Dual TCR-Expressing T Lymphocytes in Health and Disease." International Archives of Allergy and Immunology 125, no. 1 (2001): 16–20. http://dx.doi.org/10.1159/000053792.
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Torres, Pilar S., Andrés Alcover, David A. Zapata, Jacques Arnaud, Alberto Pacheco, José M. Martín-Fernández, Eugenia M. Villasevil, Ozden Sanal, and José R. Regueiro. "TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ." Journal of Immunology 170, no. 12 (June 15, 2003): 5947–55. http://dx.doi.org/10.4049/jimmunol.170.12.5947.
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Paterson, Robin K., Horst Bluethmann, Pi-ou Tseng, Anne Dunlap, and Terri H. Finkel. "Development and function of autospecific dual TCR+ T lymphocytes." International Immunology 11, no. 1 (January 1999): 113–19. http://dx.doi.org/10.1093/intimm/11.1.113.
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REGNAULT, A. "The TCR-? chain repertoire of gut-derived T lymphocytes." Seminars in Immunology 7, no. 5 (October 1995): 307–19. http://dx.doi.org/10.1016/1044-5323(95)90012-8.
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Bank, I., M. Book, L. Cohen, A. Kneller, E. Rosental, M. Pras, IB Bassat, and A. Ben-Nun. "Expansion of a unique subpopulation of cytotoxic T cells that express a C alpha V delta 1 T-cell receptor gene in a patient with severe persistent neutropenia." Blood 80, no. 12 (December 15, 1992): 3157–63. http://dx.doi.org/10.1182/blood.v80.12.3157.3157.
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Abstract CD8+ T-lymphocyte populations may be expanded in the peripheral blood of patients with chronic idiopathic neutropenia and may be involved in suppression of granulopoiesis. In this report, we have analyzed the T-cell receptor (TCR) used by the T lymphocytes of a patient with chronic severe neutropenia. Using specific oligonucleotides in the polymerase chain reaction (PCR) to amplify cDNA specific for the different families of the V alpha, V beta, and V delta TCR genes, and monoclonal antibodies (MoAbs) to examine T-lymphocyte subsets and their TCR, a persistent expansion of CD3+CD8+ T lymphocytes and a reduced repertoire of TCR V alpha and V beta genes were found in the patient's peripheral blood mononuclear cell (PBMC) preparations. A predominant portion of the T lymphocytes expressed a unique TCR structure. Thus, we found that, despite the fact that 98% of the T cells expressed alpha beta TCR on the surface membrane and less than 2% expressed tau delta TCR, nonetheless, 40% to 60% of the T cells stained positively with anti V delta 1 MoAb. Using the PCR analysis, the V delta 1 gene segment was found to be rearranged to C alpha, rather than to C delta genes. The expanded C alpha V delta 1+ cells, which are found only rarely in normal PB, expressed CD8 and were cytotoxic, and the C alpha V delta 1 receptor was functional in cytotoxicity. This constitutes the first description of an expansion of cytotoxic CD8+ lymphocytes expressing a functional “hybrid” C alpha V delta 1 gene in vivo, and suggests a pathogenic role for CD8+ C alpha V delta 1+ cells in some patients with idiopathic neutropenia.
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Bank, I., M. Book, L. Cohen, A. Kneller, E. Rosental, M. Pras, IB Bassat, and A. Ben-Nun. "Expansion of a unique subpopulation of cytotoxic T cells that express a C alpha V delta 1 T-cell receptor gene in a patient with severe persistent neutropenia." Blood 80, no. 12 (December 15, 1992): 3157–63. http://dx.doi.org/10.1182/blood.v80.12.3157.bloodjournal80123157.
Full textAbstract:
CD8+ T-lymphocyte populations may be expanded in the peripheral blood of patients with chronic idiopathic neutropenia and may be involved in suppression of granulopoiesis. In this report, we have analyzed the T-cell receptor (TCR) used by the T lymphocytes of a patient with chronic severe neutropenia. Using specific oligonucleotides in the polymerase chain reaction (PCR) to amplify cDNA specific for the different families of the V alpha, V beta, and V delta TCR genes, and monoclonal antibodies (MoAbs) to examine T-lymphocyte subsets and their TCR, a persistent expansion of CD3+CD8+ T lymphocytes and a reduced repertoire of TCR V alpha and V beta genes were found in the patient's peripheral blood mononuclear cell (PBMC) preparations. A predominant portion of the T lymphocytes expressed a unique TCR structure. Thus, we found that, despite the fact that 98% of the T cells expressed alpha beta TCR on the surface membrane and less than 2% expressed tau delta TCR, nonetheless, 40% to 60% of the T cells stained positively with anti V delta 1 MoAb. Using the PCR analysis, the V delta 1 gene segment was found to be rearranged to C alpha, rather than to C delta genes. The expanded C alpha V delta 1+ cells, which are found only rarely in normal PB, expressed CD8 and were cytotoxic, and the C alpha V delta 1 receptor was functional in cytotoxicity. This constitutes the first description of an expansion of cytotoxic CD8+ lymphocytes expressing a functional “hybrid” C alpha V delta 1 gene in vivo, and suggests a pathogenic role for CD8+ C alpha V delta 1+ cells in some patients with idiopathic neutropenia.
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Provasi, Elena, Pietro Genovese, Angelo Lombardo, Zulma Magnani, Andreas Reik, Pei-Qi Liu, Victoria Chu, et al. "Editing Human Lymphocyte Specificity for Safe and Effective Adoptive Immunotherapy of Leukemia." Blood 116, no. 21 (November 19, 2010): 3764. http://dx.doi.org/10.1182/blood.v116.21.3764.3764.
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Abstract Abstract 3764 T cell receptor (TCR) gene-transfer is an attractive strategy for the adoptive immunotherapy of tumors. However, the full potential of this approach is limited by a number of technical hurdles including inefficient gene transfer, unstable transgene expression, exhaustion of gene-modified cells and most importantly, co-expression of the endogenous and exogenous tumor-specific TCR in the same cell. The co-expression of endogenous and exogenous TCR causes not only reduced cell-surface expression of the introduced tumor-specific TCR, but also the potential for T cells to acquire autoreactive specificities due to mispairing between the different TCR chains. Mispaired TCR have been shown to be autoreactive and potentially harmful in animal models. To address these limitations, we developed a novel strategy based on zinc finger nucleases (ZFNs) that allows for the first time the editing of T cell specificity at the DNA level, by combining the disruption of the endogenous TCR chain genes with the transfer of a tumor-specific TCR. We first stimulated PBL with anti-CD3 and anti-CD28 antibody-conjugated beads, and cultured these cells in low dose IL-7/IL-15 to preserve early differentiated T cells. We transiently expressed ZFNs targeting the constant region of the TCR alpha or beta chain genes in activated T lymphocytes using a chimeric Ad5/F35 vector, thus promoting the genetic disruption of the endogenous TCR. Lymphocytes targeted by each set of ZFNs abrogated expression of the CD3/TCR complex on the cell surface. CD3neg cells could be expanded in culture with IL7 and IL15 and expressed differentiation markers typical of central memory T cells (CD62L, CD127, CD27 and CD28), indistinguishably from unmodified T cells. Sorted CD3neg cells proved stable in culture and permissive to lentiviral transduction. Indeed, introduction of exogenous TCR chains on a Lentivirus restored the expression and functionality of the CD3/TCR complex and allowed selective expansion of TCR-transduced cells by stimulation via the TCR complex. As a model TCR, we selected an HLA-A2 restricted, codon-optimized cysteine-modified TCR specific for the Wilms' tumor antigen 1 (WT1), which is expressed by several solid tumors and leukemias and contributes to the uncontrolled proliferation of cancer cells. For a complete editing of T cell specificity, we established a protocol that sequentially disrupted the endogenous TCR chains followed by lentiviral transfer of the WT1-specific TCR. This procedure resulted in a population of TCR-edited lymphocytes encoding only the tumor-specific TCR that, in the absence of competition, was expressed at high and physiological levels. Accordingly, TCR-edited lymphocytes were superior to conventional TCR-transferred cells in promoting specific recognition of WT1-expressing targets, including primary leukemias, and most importantly, were devoid of residual endogenous reactivity including alloreactivity. These data demonstrate that the successful genetic re-programming of T cell specificity in primary lymphocytes results in a functionally superior target specific killing activity and thus has the potential to greatly improve the safety and therapeutic benefit of cancer immunotherapy. (Provasi and Genovese: equal contribution). Disclosures: Reik: Sangamo: Employment. Liu:Sangamo: Employment. Chu:Sangamo: Employment. Bordignon:Molmed: Employment. Holmes:Sangamo: Employment. Gregory:Sangamo: Employment. Bonini:Molmed: Consultancy.
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Busch, Dirk H., Ingrid Pilip, and Eric G. Pamer. "Evolution of a Complex T Cell Receptor Repertoire during Primary and Recall Bacterial Infection." Journal of Experimental Medicine 188, no. 1 (July 1, 1998): 61–70. http://dx.doi.org/10.1084/jem.188.1.61.
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The mechanisms underlying the genesis and maintenance of T cell memory remain unclear. In this study, we examined the evolution of a complex, antigen-specific T cell population during the transition from primary effector to memory T cells after Listeria monocytogenes infection. T cell populations specific for listeriolysin O (LLO)91–99, the immunodominant epitope recognized by H2-Kd–restricted T lymphocytes, were directly identified in immune spleens using tetrameric H2-Kd–epitope complexes. The T cell receptor (TCR) Vβ repertoire of specific T cells was determined by direct, ex vivo staining with a panel of mAbs. We demonstrate that LLO91–99-specific, primary effector T cell populations have a diverse TCR Vβ repertoire. Analyses of memory T cell populations demonstrated similar TCR diversity. Furthermore, experiments with individual mice demonstrated that primary effector and memory T cells have indistinguishable TCR repertoires. Remarkably, after reinfection with L. monocytogenes, LLO91–99-specific T cells have a narrower TCR repertoire than do primary effector or memory T cells. Thus, our studies show that the TCR repertoire of primary effector T lymphocytes is uniformly transmitted to memory T cells, whereas expansion of memory T cells is selective.
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Casanova, J. L., J. C. Cerottini, M. Matthes, A. Necker, H. Gournier, C. Barra, C. Widmann, H. R. MacDonald, F. Lemonnier, and B. Malissen. "H-2-restricted cytolytic T lymphocytes specific for HLA display T cell receptors of limited diversity." Journal of Experimental Medicine 176, no. 2 (August 1, 1992): 439–47. http://dx.doi.org/10.1084/jem.176.2.439.
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We previously showed that H-2Kd-restricted cytotoxic T lymphocyte (CTL) clones specific for a single nonapeptide derived from the Plasmodium berghei circumsporozoite (PbCS) protein displayed T cell receptors (TCRs) of highly diverse primary structure. We have now analyzed the TCR repertoire of CTLs that recognize a peptide derived from the human class I major histocompatibility complex (MHC) molecule HLA-Cw3 in association with the same murine class I MHC molecule H-2Kd. We first sequenced the TCR alpha and beta genes of the CTL clone Cw3/1.1 and, based on this genomic analysis, the TCR alpha and beta cDNA junctional regions of 23 independent H-2Kd-restricted CTL clones specific for HLA-Cw3. The results show that the TCR chains display very limited heterogeneity, both in terms of V alpha, J alpha, V beta, and J beta segments, and in terms of length and sequence of the CDR3 alpha and beta loops. The TCR repertoire used in vivo was then analyzed by harvesting CTL populations from the peritoneal cavity of immune mice. The peritoneal exudate lymphocytes (PELs) displayed HLA-Cw3-specific cytolytic activity in the absence of any stimulation in vitro. Remarkably, most of these freshly isolated PELs expressed TCRs that shared the same structural features as those from HLA-Cw3-reactive CTL clones. Thus, our results show that a peptide from HLA-Cw3 presented by H-2Kd selects CTLs that bear TCRs of very limited diversity in vivo. When taken together with the high diversity of the TCRs specific for the PbCS peptide, these findings suggest that natural tolerance to self peptides presented by class I MHC molecules may substantially reduce the size of the TCR repertoire of CTLs specific for antigenic peptides homologous to self.
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Irles, Claudine, Joel Arias-Martinez, José Guzmán-Bárcenas, and Alicia Ortega. "Plasma membrane subdomain partitioning of Lck in primary human T lymphocytes." Canadian Journal of Physiology and Pharmacology 88, no. 4 (April 2010): 487–96. http://dx.doi.org/10.1139/y09-125.
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Uncovering the plasma membrane distribution of tyrosine kinase Lck is crucial to understanding T lymphocyte triggering. Several studies of Lck species partitioning have given contradictory results. We decided to re-address this point by using phospho-specific antibodies to characterize active and inactive Lck partitioning in raft and non-raft membranes from primary human peripheral blood T lymphocytes. We show that most inactive Lck was localized in rafts and was associated with nearly all CD4 coreceptors and its negative regulator Csk in resting cells, while T cell receptor (TCR) engagement promoted a sustained dephosphorylation of inactive Lck. In contrast, active Lck had a more discrete distribution interacting with only a small number of CD4 coreceptors, and the kinase showed a rapid and short phosphorylation after TCR triggering. The differences in distribution and kinetics may be related to T lymphocyte signalling threshold modulation by Lck species and suggest how TCR triggering is first initiated. This study furthers our knowledge of the TCR activation model in primary human T lymphocytes.
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Wahl, Astrid, Céline Dinet, Pierre Dillard, Aya Nassereddine, Pierre-Henri Puech, Laurent Limozin, and Kheya Sengupta. "Biphasic mechanosensitivity of T cell receptor-mediated spreading of lymphocytes." Proceedings of the National Academy of Sciences 116, no. 13 (March 8, 2019): 5908–13. http://dx.doi.org/10.1073/pnas.1811516116.
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Mechanosensing by T cells through the T cell receptor (TCR) is at the heart of immune recognition. While the mechanobiology of the TCR at the molecular level is increasingly well documented, its link to cell-scale response is poorly understood. Here we explore T cell spreading response as a function of substrate rigidity and show that remarkably, depending on the surface receptors stimulated, the cellular response may be either biphasic or monotonous. When adhering solely via the TCR complex, T cells respond to environmental stiffness in an unusual fashion, attaining maximal spreading on an optimal substrate stiffness comparable to that of professional antigen-presenting cells. However, in the presence of additional ligands for the integrin LFA-1, this biphasic response is abrogated and the cell spreading increases monotonously with stiffness up to a saturation value. This ligand-specific mechanosensing is effected through an actin-polymerization–dependent mechanism. We construct a mesoscale semianalytical model based on force-dependent bond rupture and show that cell-scale biphasic or monotonous behavior emerges from molecular parameters. As the substrate stiffness is increased, there is a competition between increasing effective stiffness of the bonds, which leads to increased cell spreading and increasing bond breakage, which leads to decreased spreading. We hypothesize that the link between actin and the receptors (TCR or LFA-1), rather than the ligand/receptor linkage, is the site of this mechanosensing.
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Lev, Atar, Amos J. Simon, Luba Trakhtenbrot, Itamar Goldstein, Meital Nagar, Polina Stepensky, Gideon Rechavi, Ninette Amariglio, and Raz Somech. "Characterizing T Cells in SCID Patients Presenting with Reactive or Residual T Lymphocytes." Clinical and Developmental Immunology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/261470.
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Introduction. Patients with severe combined immunodeficiency (SCID) may present with residual circulating T cells. While all cells are functionally deficient, resulting in high susceptibility to infections, only some of these cells are causing autoimmune symptoms.Methods. Here we compared T-cell functions including the number of circulating CD3+T cells,in vitroresponses to mitogens, T-cell receptor (TCR) repertoire, TCR excision circles (TREC) levels, and regulatory T cells (Tregs) enumeration in several immunodeficinecy subtypes, clinically presenting with nonreactive residual cells (MHC-II deficiency) or reactive cells. The latter includes patients with autoreactive clonal expanded T cell and patients with alloreactive transplacentally maternal T cells.Results. MHC-II deficient patients had slightly reduced T-cell function, normal TRECs, TCR repertoires, and normal Tregs enumeration. In contrast, patients with reactive T cells exhibited poor T-cell differentiation and activity. While the autoreactive cells displayed significantly reduced Tregs numbers, the alloreactive transplacentally acquired maternal lymphocytes had high functional Tregs.Conclusion. SCID patients presenting with circulating T cells show different patterns of T-cell activity and regulatory T cells enumeration that dictates the immunodeficient and autoimmune manifestations. We suggest that a high-tolerance capacity of the alloreactive transplacentally acquired maternal lymphocytes represents a toleration advantage, yet still associated with severe immunodeficiency.