Obarorakpor, NyerhovwoPatel, DeepBoyarov, ReniAmarsaikhan, NansalmaaCepeda, Joseph RayEastes, DoreenRobertson, SylviaJohnson, TravisYang, KaiTang, QizhiZhang, Li2024-02-282024-02-282023-08-01Obarorakpor N, Patel D, Boyarov R, et al. Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes. Front Immunol. 2023;14:1207108. Published 2023 Aug 1. doi:10.3389/fimmu.2023.1207108https://hdl.handle.net/1805/38970Introduction: In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. Methods: To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. Results: InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.en-USAttribution 4.0 InternationalType 1 diabetesRegulatory T cellChimeric antigen receptorAntigen specific immunotherapyMHC II/Insulin complexMonoclonal antibodyArticle