Brian T Fife
Center for Immunology, University of Minnesota, USAPresentation Title:
CD4+ T cells reactive to a hybrid peptide from insulin-chromogranin A adopt a distinct effector fate and are pathogenic in autoimmune diabetes
Abstract
T cell-mediated islet destruction is a
hallmark of autoimmune diabetes. Here, we examined the dynamics and
pathogenicity of CD4+ T cell responses to four different insulin-derived
epitopes during diabetes initiation in non-obese diabetic (NOD) mice. Single-cell
RNA sequencing of tetramer-sorted CD4+ T cells from the pancreas revealed that
islet-antigen-specific T cells adopted a wide variety of fates and required
XCR1+ dendritic cells for their activation. Hybrid-insulin C-chromogranin A
(InsC-ChgA)-specific CD4+ T cells skewed toward a distinct T helper type 1
(Th1) effector phenotype, whereas the majority of insulin B chain and
hybrid-insulin C-islet amyloid polypeptide-specific CD4+ T cells exhibited a
regulatory phenotype and early or weak Th1 phenotype, respectively.
InsC-ChgA-specific CD4+ T cells were uniquely pathogenic upon transfer, and an
anti-InsC-ChgA:IAg7 antibody prevented spontaneous diabetes. Our findings
highlight the heterogeneity of T cell responses to insulin-derived epitopes in
diabetes and argue for the feasibility of antigen-specific therapies that
blunts the response of pathogenic CD4+ T cells causing autoimmunity.
Biography
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