Central and peripheral tolerance shape distinct fate decisions and differential pathogenicity among CD4 T cells specific for disparate hybrid insulin peptides during autoimmune diabetes 3705

Abstract Description CD4 T cells targeting hybrid insulin peptides have been found in the pancreas of both mice and humans with autoimmune diabetes. Monoclonal T cells reactive to hybrid insulin peptides derived from insulin and chromogranin A (InsC-ChgA) or islet amyloid polypeptide (InsC-IAPP) are pathogenic in NOD mice. We sought to determine how tolerance shapes the fate and pathogenic potential of polyclonal CD4 T cells responding to hybrid insulin peptides. We discovered that nearly all T cells in NOD mice responding to InsC-ChgA become activated within 3 weeks of life, whereas T cells responding to InsC-IAPP become maximally activated at 8 weeks of life, with ∼30% of cells remaining naïve throughout adulthood. Within the pancreas, the InsC-ChgA-specific cells showed a strong preference towards Th1 while InsC-IAPP-specific cells were enriched for Il-10 expressing FOXP3- cells. Both populations of cells had a low frequency (<10%) of FOXP3+ regulatory T cells. XCR1+ dendritic cells were required for the activation of InsC-ChgA-specific cells early in life but dispensable by 10 weeks of life. T cell receptor sequencing revealed that both InsC-ChgA and InsC-IAPP-specific cells have highly restricted repertoires, including public clonotypes. Overall, these data show that central tolerance and inflammation-induced alterations in antigen processing and presentation shape the fate of hybrid insulin peptide-specific T cells, impacting their capacity to induce autoimmunity. Funding Sources Supported by NIH RO1 AI06791; NIH RO1 AI156276; NIH R21 AI166475; NIH PO1 AI35296; The Leona M. and Harry B. Helmsley Charitable Trust 2018PG-T1D058, G-2303-06775, G2405-06927 Topic Categories Basic Autoimmunity (BA)