Type 1 diabetes is an autoimmune-mediated disease that culminates in the targeted destruction of insulin-producing β-cells. CD4 responses in NOD mice are dominated by insulin epitope B:9-23 (InsB9-23) specificity, and mutation of the key T-cell receptor (TCR) contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and regulatory T cells (Tregs). Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality, and pathogenicity of insulin-specific T cells that develop in the absence of cognate antigen. Using a single TCR system, we demonstrate that Treg development is greatly diminished in mice with the Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB9-23 by both limiting the development of pathogenic T cells and supporting the selection of Tregs.

中文翻译：

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关键的胰岛素 TCR 接触残留物选择高亲和力和致病性胰岛素特异性 T 细胞


1 型糖尿病是一种自身免疫介导的疾病，最终导致产生胰岛素的 β 细胞遭到有针对性的破坏。 NOD 小鼠中的 CD4 反应主要由胰岛素表位 B:9-23 (InsB9-23) 特异性决定，表位内关键 T 细胞受体 (TCR) 接触残基的突变可预防糖尿病的发生。然而，尚不清楚胰岛素自身抗原如何控制自身免疫和调节性 T 细胞 (Treg) 的选择。在这里，我们证明胰岛素表位突变会导致高致病性 T 细胞逃逸。我们观察到在没有同源抗原的情况下发育的胰岛素特异性 T 细胞的抗原反应性、克隆性和致病性增加。使用单一 TCR 系统，我们证明具有 Y16A 突变表位的小鼠中 Treg 发育大大减少。总的来说，这些结果表明，16 位的酪氨酸残基对于通过限制致病性 T 细胞的发育和支持 Tregs 的选择来限制 InsB9-23 的 TCR 反应性是必要的。