| First Author | Mitchell JS | Year | 2024 |
| Journal | Immunity | Volume | 57 |
| Issue | 10 | Pages | 2399-2415.e8 |
| PubMed ID | 39214091 | Mgi Jnum | J:355474 |
| Mgi Id | MGI:7750194 | Doi | 10.1016/j.immuni.2024.07.024 |
| Citation | Mitchell JS, et al. (2024) CD4(+) T cells reactive to a hybrid peptide from insulin-chromogranin A adopt a distinct effector fate and are pathogenic in autoimmune diabetes. Immunity 57(10):2399-2415.e8 |
| abstractText | 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. |
