Human CD4 T cells recognize the c-terminally modified insulin B:9-23 peptide in the same fashion as mouse diabetogenic T cells

Human CD4 T cells recognize the c-terminally modified insulin B:9-23 peptide in the same fashion as mouse diabetogenic T cells

Yang Wang1,2, Tomasz Sosinowski3, Andrey Novikov1, Frances Crawford4, Howard W. Davidson2,3, Laurent Gapin2, John Kappler2,4, and Shaodong Dai1,2

1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus & 2 Department of Immunology and Microbiology School of Medicine, University of Colorado Anschutz Medical Campus; Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus ; 4 Department of Biomedical Research, National Jewish Health

Background: The risk of developing type 1 diabetes (T1D) is closely linked to polymorphisms in major histocompatibility complex class II (MHCII) genes. In humans, the highest T1D genetic risk factor is a single polymorphism in the β chain of HLA-DQ (DQ) within the codon for β57. CD4 T cells respond to the insulin B:9-23 peptide in both mice and humans. We previously showed that C-terminal amino acids changes to this peptide are required for proper binding to MHC and recognition by T cells.

Methods: We used a collection of previously described NOD mouse and human CD4 T cell clones that respond poorly to the natural insulin B:9-23 peptide presented by either IAg7 or DQ8. We constructed various versions of the insulin peptide bearing mutations to assure binding in register 3 (R3). We determined the structures of a mouse Type A, a mouse Type B and a human TCR, bound to their optimal versions of the R3 insulin peptide-MHCII ligands.

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Results: The structures showed that the specificity differences among mouse Type A and Type B T cells lies in how they deal with the amino acid at p8 of the insulin peptide. Despite differences among the mouse and human TCRs in the sequences of their Vα and Vβ domains and their orientations on their ligands, there were some striking common features to the complexes pointing out the similarities in human and mouse both in how these ligands are formed and in how TCRs engage them. The structures also show how the peptide modifications were essential to the formation of the complexes, suggesting a role for modification of the peptide in vivo to initiate the CD4 T cell response in T1D. Our data provide an explanation for how diabetogenic T cells escape negative selection in the thymus.