HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis

2018 ◽  
Vol 45 (7) ◽  
pp. 905-914 ◽  
Author(s):  
Keiichi Sakurai ◽  
Kazuyoshi Ishigaki ◽  
Hirofumi Shoda ◽  
Yasuo Nagafuchi ◽  
Yumi Tsuchida ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Activity ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Shared Epitope ◽  
Cell Receptor ◽  
Allele Dosage ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Memory Cd4 T Cells

Objective.Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS).Methods.The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA.Results.The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels.Conclusion.SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.

scholarly journals Characterization of T-Cell Receptor Repertoire in Patients with Rheumatoid Arthritis Receiving Biologic Therapies

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Che-Mai Chang ◽  
Yu-Wen Hsu ◽  
Henry Sung-Ching Wong ◽  
James Cheng-Chung Wei ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Disease Activity ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Therapeutic Effects ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Tcr Repertoire ◽  
Repertoire Diversity

Rheumatoid arthritis (RA) is a systematic autoimmune disease, predominantly causing chronic polyarticular inflammation and joint injury of patients. For the treatment of RA, biologic disease-modifying antirheumatic drugs (bDMARDs) have been used to reduce inflammation and to interfere with disease progression through targeting and mediating the immune system. Although the therapeutic effects of bDMARDs in RA patients have been widely reported, whether these drugs also play important roles in T-cell repertoire status is still unclear. We therefore designed the study to identify the role of T-cell repertoire profiles in RA patients with different types of bDMARD treatments. A high-throughput sequencing approach was applied to profile the T-cell receptor beta chain (TCRB) repertoire of circulating T lymphocytes in eight patients given adalimumab (anti-TNF-α) with/without the following use of either rituximab (anti-CD20) or tocilizumab (anti-IL6R). We subsequently analyzed discrepancies in the clonal diversity and CDR3 length distribution as well as usages of the V and J genes of TCRB repertoire and interrogated the association between repertoire diversity and disease activities followed by the treatment of bDMARDs in these RA patients. All groups of patients showed well-controlled DAS28 scores (<2.6) after different treatment regimens of drugs and displayed no significant statistical differences in repertoire diversity, distribution of CDR3 lengths, and usage of V and J genes of TCRB. Nonetheless, a trend between overall TCRB repertoire diversity and disease activity scores in all bDMARD-treated RA patients was observed. Additionally, age was found to be associated with repertoire diversity in RA patients treated with bDMARDs. Through the profiling of the TCR repertoire in RA patients receiving different biologic medications, our study indicated an inverse tendency between TCR repertoire diversity and disease activity after biologic treatment in RA patients.

scholarly journals Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor

2001 ◽  
Vol 194 (6) ◽  
pp. 719-732 ◽  
Author(s):  
Saied Mirshahidi ◽  
Ching-Tai Huang ◽  
Scheherazade Sadegh-Nasseri
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Critical Role ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Memory Cd4 T Cells

Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4+ T cells can be rendered anergic by presentation of low densities of agonist peptide–major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2–reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti–CTLA-4 blocking antibody restored anergy in vivo.

scholarly journals High Level Expression of Cd43 Inhibits T Cell Receptor/CD3-Mediated Apoptosis

1999 ◽  
Vol 190 (12) ◽  
pp. 1903-1908 ◽  
Author(s):  
You-Wen He ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Cell Phenotype ◽  
High Level Expression ◽  
High Level ◽  
Memory Cd4 T Cells

In a screen designed to identify genes that regulate T cell receptor (TCR)/CD3-mediated apoptosis, we found that high level expression of CD43 protected T cell hybridomas from activation-induced cell death. The protection appears to result from its capacity to block Fas-mediated death signals rather than from inhibition of the upregulation of Fas and/or Fas ligand after T cell stimulation. We found that peripheral CD4+ T cells can be divided into two subsets based on the level of CD43 surface expression. The CD4+CD43low subset exhibits a naive T cell phenotype, being CD62LhighCD45RBhighCD44low, whereas CD4+CD43high cells exhibit a memory phenotype, being CD62LlowCD45RBlowCD44high. Recent studies have demonstrated that engagement of TCR and Fas induces naive CD4+ T cells to undergo apoptosis, and the same treatment enhances the proliferation of memory CD4+ T cells. We confirm here that peripheral CD4+CD43high T cells are resistant to TCR/CD3-mediated cell death. These results suggest that the expression levels of CD43 on naive and memory CD4+ T cells determine their susceptibility to Fas-dependent cell death and that high level expression of CD43 may be used as a marker to define CD4+ memory T cells. Expression of CD43 provides a novel mechanism by which tumor cells expressing abnormally high levels of CD43 may escape Fas-mediated killing.

scholarly journals Human γδ TCR Repertoires in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 800 ◽  
Author(s):  
Alina Suzann Fichtner ◽  
Sarina Ravens ◽  
Immo Prinz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Γδ T Cell ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Health And Disease ◽  
Αβ T Cells

The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.

scholarly journals Shared T cell receptor chains in blood memory CD4+ T cells of narcolepsy type 1 patients

2019 ◽  
Vol 100 ◽  
pp. 1-6 ◽  
Author(s):  
Eduardo Beltrán ◽  
Xuan-Hung Nguyen ◽  
Clémence Quériault ◽  
Lucie Barateau ◽  
Yves Dauvilliers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Memory Cd4 T Cells

Differential T cell receptor-mediated signaling in naive and memory CD4 T cells

1997 ◽  
Vol 27 (8) ◽  
pp. 2094-2101 ◽  
Author(s):  
Donna L. Farber ◽  
Oreste Acuto ◽  
Kim Bottomly
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Memory Cd4 T Cells

scholarly journals Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire

2010 ◽  
Vol 208 (1) ◽  
pp. 3-11 ◽  
Author(s):  
Christophe Viret ◽  
Camille Lamare ◽  
Martine Guiraud ◽  
Nicolas Fazilleau ◽  
Agathe Bour ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Serine Protease ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Tcr Repertoire ◽  
Deficient Mice

Thymus-specific serine protease (TSSP) is a novel protease that may contribute to the generation of the peptide repertoire presented by MHC class II molecules in the thymus. Although TSSP deficiency has no quantitative impact on the development of CD4 T cells expressing a polyclonal T cell receptor (TCR) repertoire, the development of CD4 T cells expressing the OTII and Marilyn transgenic TCRs is impaired in TSSP-deficient mice. In this study, we assess the role of TSSP in shaping the functional endogenous polyclonal CD4 T cell repertoire by analyzing the response of TSSP-deficient mice to several protein antigens (Ags). Although TSSP-deficient mice responded normally to most of the Ags tested, they responded poorly to hen egg lysozyme (HEL). The impaired CD4 T cell response of TSSP-deficient mice to HEL correlated with significant alteration of the dominant TCR-β chain repertoire expressed by HEL-specific CD4 T cells, suggesting that TSSP is necessary for the intrathymic development of cells expressing these TCRs. Thus, TSSP contributes to the diversification of the functional endogenous CD4 T cell TCR repertoire in the thymus.

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