Research ArticleAUTOIMMUNITY

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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Science Immunology  30 Aug 2019:
Vol. 4, Issue 38, eaaw6329
DOI: 10.1126/sciimmunol.aaw6329

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Insulin peptide recognition by early diabetogenic T cells

Type 1 diabetes is initiated by loss of T cell tolerance to pancreatic islet autoantigens including insulin. Gioia et al. developed peptide-MHC tetramer reagents capable of distinguishing separate populations of insulin-reactive CD4+ T cells from diabetes-prone NOD mice that differ in the register used for insulin peptide binding to class II MHC. Analysis of pancreatic islet tissue using these tetramers revealed that the earliest phase of the anti-insulin T cell response in islets is dominated by T cells with TCR sequence modifications that enable recognition of an Ins12–20 peptide–MHC class II complex. Identification of the primary mode of peptide recognition used by the early anti-insulin T cells opens the door to designing inhibitors capable of selectively blocking activation of these rogue T cells.

Abstract

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-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 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 TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, 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 TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 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.

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