CD4+ T cells reactive to a hybrid peptide from insulin-chromogranin A adopt a distinct effector fate and are pathogenic in autoimmune diabetes 4639
Year: 2025
Type: article
Abstract: Description 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. Funding Sources (NIH) R01AI106791 (to B.T.F.), R01 AI156276 (to B.T.F.), R21AI166475 (to B.T.F.), P01AI35296 (to B.T.F.); The Leona M. and Harry B. Helmsley Charitable Trust 2018PGT1D058 (to B.T.F.), G-2303-06775 (to B.T.F.); the Minnesota Lions Diabetes Foundation and University of Minnesota Foundation Fund 11724. Topic Categories Basic Autoimmunity (BA)
Source: The Journal of Immunology
Author: Brian T. Fife
Institution: University of Minnesota
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416450950
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