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+CD127-FOXP3+ 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+CD127-FOXP3+ regulatory T cells.

中文翻译：

---

具有1型糖尿病保护单倍型的健康个体的胰岛抗原特异性调节和效应CD4 + T细胞增加。

DRB1 * 15：01-DQB1 * 06：02（DR1501-DQ6）单倍型与1型糖尿病的主要保护作用相关，但这种关联的细胞机制尚不清楚。为了解决这个问题，我们鉴定了多个DR1501和DQ6限制性谷氨酸脱羧酶65（GAD65）和胰岛特异性葡萄糖-6磷酸酶催化亚基相关蛋白（IGRP）特异性T细胞表位。先前报道，鉴定出的三个受DR1501 / DQ6限制的表位受DRB1 * 04：01 / DRB1 * 03：01 / DQB1 * 03：02的限制。我们还使用了特定的II类四聚体试剂来评估T细胞频率。我们的结果表明，具有保护性单倍型个体的GAD65特异性和IGRP特异性效应子以及CD25 + CD127-FOXP3 +调节性CD4 + T细胞的频率高于易感或中性单倍型个体。我们通过CD154 / CD137上调测定进一步证实了DR1501-DQ6个体中胰岛抗原特异性效应子和CD4 + T细胞的调节频率更高。DR1501限制的效应T细胞能够产生干扰素-γ（IFN-γ）和白介素4（IL-4），但与具有易感单倍型个体的效应子相比，更可能产生IL-10。为了评估其抗原特异性调控活性的能力，我们克隆了GAD65和IGRP表位特异性调控T细胞。我们表明，这些调节性T细胞以抗原特异性方式抑制了DR1501限制性GAD65和IGRP特异性效应子和DQB1 * 03：02限制性GAD65特异性效应子。总共，