biostudies-literatureGioia LNational Institutes of Healtheaaw6329https://www.ebi.ac.uk/biostudies/studies/S-EPMC6816460biostudies-literatureUnknown4(38)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 Science immunologyPosition β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset.PMC6816460UL1TR002550, TL1TR0025511R01DK117138R01DK099317DK097605 and DK107541RO1DK058177UL1TR002550, KL2TR001112Sharma SAbe BKain LSu AGioia LMathews CUnanue EWan XHolt MChen YGCostanzo ATeyton LNakayama MfalsePosition β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset.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 2019-01-01T00:00:00Z2019 Aug2025-05-31T23:54:08.726Z2025-05-31T23:54:08.726ZS-EPMC68164603147135210.1126/sciimmunol.aaw6329