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Position I?57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset. Sci Immunol 2019 08 30;4(38)

Date

09/01/2019

Pubmed ID

31471352

Pubmed Central ID

PMC6816460

DOI

10.1126/sciimmunol.aaw6329

Scopus ID

2-s2.0-85071762036   14 Citations

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-DQI? 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 TCRI?I? pairs in vitro. Genetic correction of the I-AI?57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3I? 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.

Author List

Gioia L, Holt M, Costanzo A, Sharma S, Abe B, Kain L, Nakayama M, Wan X, Su A, Mathews C, Chen YG, Unanue E, Teyton L

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alleles
Animals
CD4-Positive T-Lymphocytes
Cell Line
Diabetes Mellitus, Type 1
Female
Insulin
Major Histocompatibility Complex
Mice
Mice, Inbred NOD
Peptides
Receptors, Antigen, T-Cell