Increased islet antigen–specific regulatory and effectorCD4+ T cells in healthy individuals with the type 1diabetes–protective haplotype

摘要

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, butthe cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- andDQ6-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 previouslyreported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramerreagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+ CD127 FOXP3+ regulatory CD4+T cells were present at higher frequencies in individuals with the protective haplotypethan 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- (IFN-) and interleukin-4 (IL-4) but weremore likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluatetheir 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+CD127 FOXP3+ regulatory T cells.