Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset
Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset
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DOI：
10.1126/sciimmunol.aaw6329
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发表时间：
2019-08-01
影响因子：
24.8
通讯作者：
Teyton, Luc
中科院分区：
文献类型：
--
作者：
Gioia, Louis;Holt, Marie;Teyton, Luc
主要组织相容性复合体（MHC）位点的II类区域是1型糖尿病（T1D）遗传易感性的主要因素。糖尿病源性HLA-DQ β链第57位天门氨酸的缺失支持了这种关联；这种单一氨基酸的变化通过一种称为P9开关的机制影响tcr在HLA-DQ8和I-A（g7）背景下识别肽的方式。在这里，我们构建了注册特异性胰岛素肽MHC四聚体，以检测非肥胖糖尿病（NOD）小鼠早期糖尿病前期CD4(+) T细胞对Ins（12-20）和Ins（13-21）肽的反应。在6周龄和12周龄NOD小鼠中进行的抗胰岛素CD4(+) T细胞单细胞分析显示了组织特异性基因表达特征。TCR信号传导和克隆扩增仅在朗格汉斯胰岛中发现，并产生经典的T(H)1分化或不寻常的T-reg表型，与TCR的使用无关。抗胰岛素应答的早期阶段是由特异性的T细胞主导的（12-20），该寄存器支持P9开关识别模式。通过TCR测序、重表达、诱变和体外TCR α - β对的功能测试，证实了P9开关的存在。NOD小鼠I-A β 57突变的基因校正导致抗- ins (12-20) T细胞CDR3 β中D/E残基的消失。这些结果提供了一种机制分子解释，将T1D的MHC II类多态性特征与胰岛自身抗原的识别和疾病的发病联系起来。
The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQ beta chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-A(g7) using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4(+) T cell responses to Ins(12-20) and Ins(13-21) peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4(+) T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical T(H)1 differentiation or an unusual T-reg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins(12-20), the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCR alpha beta pairs in vitro. Genetic correction of the I-A beta 57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3 beta of anti-Ins(12-20) T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.