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CD8⁺ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage.

ABSTRACT: CD8⁺ T cells directed against beta cell autoantigens are considered relevant for the pathogenesis of type 1 diabetes. Using single cell T cell receptor sequencing of CD8⁺ T cells specific for the IGRP_265-273 epitope, we examined whether there was expansion of clonotypes and sharing of T cell receptor chains in autoreactive CD8⁺ T cell repertoires. HLA-A*0201 positive type 1 diabetes patients (n?=?19) and controls (n?=?18) were analysed. TCR ?- and ?-chain sequences of 418 patient-derived IGRP_265-273-multimer⁺ CD8⁺ T cells representing 48 clonotypes were obtained. Expanded populations of IGRP_265-273-specific CD8⁺ T cells with dominant clonotypes that had TCR ?-chains shared across patients were observed. The SGGSNYKLTF motif corresponding to TRAJ53 was contained in 384 (91.9%) cells, and in 20 (41.7%) patient-derived clonotypes. TRAJ53 together with TRAV29/DV5 was found in 15 (31.3%) clonotypes. Using next generation TCR ?-chain sequencing, we found enrichment of one of these TCR ?-chains in the memory CD8⁺ T cells of patients as compared to healthy controls. CD8⁺ T cell clones bearing the enriched motifs mediated antigen-specific target cell lysis. We provide the first evidence for restriction of T cell receptor motifs in the alpha chain of human CD8⁺ T cells with specificity to a beta cell antigen.

SUBMITTER: Fuchs YF

PROVIDER: S-EPMC5353542 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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CD8+ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage.

Fuchs Yannick F YF Eugster Anne A Dietz Sevina S Sebelefsky Christian C Kühn Denise D Wilhelm Carmen C Lindner Annett A Gavrisan Anita A Knoop Jan J Dahl Andreas A Ziegler Anette-G AG Bonifacio Ezio E

Scientific reports 20170316

CD8+ T cells directed against beta cell autoantigens are considered relevant for the pathogenesis of type 1 diabetes. Using single cell T cell receptor sequencing of CD8+ T cells specific for the IGRP265-273 epitope, we examined whether there was expansion of clonotypes and sharing of T cell receptor chains in autoreactive CD8+ T cell repertoires. HLA-A*0201 positive type 1 diabetes patients (n = 19) and controls (n = 18) were analysed. TCR α- and β-ch ...[more]

PMID: 28300170

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Project description:Aims/hypothesisThe aim of this study was to characterise islet autoantibody profiles and immune cell phenotypes in slow progressors to type 1 diabetes.MethodsImmunological variables were compared across peripheral blood samples obtained from slow progressors to type 1 diabetes, individuals with newly diagnosed or long-standing type 1 diabetes, and healthy individuals. Polychromatic flow cytometry was used to characterise the phenotypic attributes of B and T cells. Islet autoantigen-specific B cells were quantified using an enzyme-linked immunospot (ELISpot) assay and islet autoantigen-specific CD8+ T cells were quantified using peptide-HLA class I tetramers. Radioimmunoassays were used to detect islet autoantibodies. Sera were assayed for various chemokines, cytokines and soluble receptors via ELISAs.ResultsIslet autoantibodies were lost over time in slow progressors. Various B cell subsets expressed higher levels of CD95 in slow progressors, especially after polyclonal stimulation, compared with the corresponding B cell subsets in healthy donors (p < 0.05). The phenotypic characteristics of CD4+ and CD8+ T cells were similar in slow progressors and healthy donors. Lower frequencies of CD4+ T cells with a central memory phenotype (CD27int, CD127+, CD95int) were observed in slow progressors compared with healthy donors (mean percentage of total CD4+ T cells was 3.00% in slow progressors vs 4.67% in healthy donors, p < 0.05). Autoreactive B cell responses to proinsulin were detected at higher frequencies in slow progressors compared with healthy donors (median no. of spots was 0 in healthy donors vs 24.34 in slow progressors, p < 0.05) in an ELISpot assay. Islet autoantigen-specific CD8+ T cell responses were largely absent in slow progressors and healthy donors. Serum levels of DcR3, the decoy receptor for CD95L, were elevated in slow progressors compared with healthy donors (median was 1087 pg/ml in slow progressors vs 651 pg/ml in healthy donors, p = 0.06).Conclusions/interpretationIn this study, we found that slow progression to type 1 diabetes was associated with a loss of islet autoantibodies and a distinct B cell phenotype, consistent with enhanced apoptotic regulation of peripheral autoreactivity via CD95. These phenotypic changes warrant further studies in larger cohorts to determine their functional implications.

Dataset Information

CD8⁺ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage.

Publications

CD8<sup>+</sup> T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage.

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