Engineering CAR Tregs for type 1 diabetes

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Summary Type 1 diabetes (T1D) results from a breakdown in immunological tolerance and the resulting T cell- mediated destruction of insulin producing beta cells in the pancreas. This is caused by defective “regulatory” T cells (or Tregs), which normally suppress harmful immune responses. In T1D, Tregs stop protecting beta cells. Work from T1D animal models has shown that therapeutic restoration of Tregs can prevent disease progression, and clinical studies have shown the safety of this approach in humans. Despite this initial success, there are significant hurdles for long term and global Treg therapy in T1D. Current methods infuse large numbers of polyclonal Tregs that have not been selected for antigen specificity, so they carry the risk of non-specific immunosuppression. Furthermore, it is difficult to expand enough of these polyclonal Tregs required for therapy, and even then, only a small fraction of the cells actually suppress autoimmunity. These challenges can be solved by creating “designer” Tregs that are engineered for specificity and have the best chance of resetting immune tolerance. If successful, this technology would lead to a more personalized and effective T1D immunotherapy. We recently developed an approach to engineer antigen-specific Tregs by re-directing their specificity using chimeric antigen receptors, or CARs. In this application, we will test if peptide specific MHC-CAR-Tregs prevent and/or reverse T1D in NOD mice. We hypothesize that mouse Tregs expressing a hybrid insulin peptide-MHCII- specific CAR will prevent T1D by restoring immune tolerance and suppressing autoreactive effector CD4+ and CD8+ T cell function to limit their accumulation in the pancreas.