Research ArticleAUTOIMMUNITY

Increased islet antigen–specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes–protective haplotype

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Science Immunology  14 Feb 2020:
Vol. 5, Issue 44, eaax8767
DOI: 10.1126/sciimmunol.aax8767

Dominant protection against type 1 diabetes

Polymorphic histocompatibility genes in the HLA locus have a strong influence on genetic susceptibility to type 1 diabetes (T1D). Several high-risk HLA haplotypes increase susceptibility to T1D, whereas the DR1501-DQ6 HLA haplotype confers dominant protection. Wen et al. investigated the mechanistic basis for this protective effect by measuring the frequency of CD4+ T cells reactive with epitopes on islet autoantigens in healthy individuals. Individuals with the protective HLA haplotype had a higher frequency of islet antigen–reactive CD4+ T cells than individuals with high-risk or neutral haplotypes. These CD4+ T cells included both regulatory T cells and effector T cells with a propensity to make IL-10. These findings provide deeper insights into how beneficial subsets of self-reactive T cells maintain prophylaxis against autoimmunity.

Abstract

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP)–specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen–specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope–specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10–producing T effectors and CD25+CD127FOXP3+ regulatory T cells.

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