CD4+ T cells targeting a hybrid insulin:chromogranin A self-antigen are necessary and sufficient for autoimmune diabetes initiation

Abstract

Abstract Autoimmune diabetes induction requires CD4+ T cell responses directed against pancreatic islet self-antigens, and recent evidence implicates insulin C-chain:chromogranin A (InsC-ChgA) hybrid peptides as critical targets. Despite suggested contributions of InsC-ChgA-specific CD4+ T cells to diabetes pathology, the mechanisms underlying antigen encounter and pathogenicity are not understood. Here, we demonstrate these cells are absent in pancreata of adult diabetes-resistant mice, yet undergo rapid activation and expansion in neonatal non-obese diabetic (NOD) mice. InsC-ChgA-specific cells were clonally restricted to a public TRBV15 CDR3 sequence paired with shared α-chains in multiple mice, and the expansion of these cells was dependent upon early interactions with XCR1+ type 1 conventional dendritic cells. We also demonstrate pathogenicity upon transfer of InsC-ChgA-specific cells into NOD.Rag1−/− mice and disease abrogation with therapeutic administration of an anti-InsC-ChgA:I-Ag7 monoclonal antibody. Most importantly, this antibody prevents spontaneous diabetes. Together, these data establish the pathogenicity of InsC-ChgA-specific cells, demonstrating sufficiency and necessity for autoimmune diabetes. Supported by grants from NIH (R01 AI156276, P01 AI35296, 2T32 AI007313)