Antigen-specific suppression of diabetogenic CD4+ T cells using engineered regulatory T cells 3315

Abstract Description Type 1 Diabetes (T1D) is an autoimmune disease in which T cells destroy insulin-producing β cells. With no cure available, many have looked to harness regulatory T cells (Tregs) as a cellular therapy to restore tolerance. Unfortunately, polyclonal Treg infusions have had limited clinical efficacy, likely due to the lack of antigen-specificity. To confer antigen-specificity, we engineered Tregs to express Signaling and Antigen-presenting Bifunctional Receptors (SABRs). SABRs are chimeric receptors that contain an extracellular peptide-MHC domain and intracellular CD3ζ-CD28 signaling domains. This receptor enables SABR-Tregs to directly engage with autoreactive CD4+ T cells. Therefore, we hypothesize that SABR-Tregs can delay or prevent T1D by antigen-specific suppression of autoreactive CD4+ T cells. To test our hypothesis, we engineered Tregs from non-obese diabetic (NOD) mice to express SABRs presenting diabetogenic autoantigens. In vitro, we demonstrate that SABR-Tregs mediate antigen-specific suppression of autoreactive CD4+ T cells. In preliminary studies, SABR-Tregs were able to delay diabetes in NOD mice. We are actively exploring ways to enhance in vivo suppression and survival of SABR-Tregs. Future work aims to characterize the mechanisms of suppression, define the in vivo protection afforded by targeting multiple autoantigen-specificities, and to test the efficacy of human SABR-Tregs. These studies pave the way for SABR-Tregs as a novel way to suppress autoimmunity. Funding Sources Supported by: NIH/National Institute of Allergy and Infectious Diseases 1DP2AI176138-01; JDRF 3-SRA-2023-1354-S-B. Topic Categories Therapeutic Approaches to Autoimmunity (THER)