CAR Treg cells mediate linked suppression and infectious tolerance in islet transplantation in mice

Regulatory T cells (T_reg cells) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using a human leukocyte antigen (HLA)–A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR T_reg cells can limit anti–HLA-A2 alloimmunity. However, it was unknown whether A2-CAR T_reg cells could also limit immunity to autoantigens. Using a model of HLA-A2⁺ islet transplantation into immunodeficient nonobese diabetic mice, we investigated whether A2-CAR T_reg cells could control hyperglycemia induced by diabetogenic BDC2.5 effector T cells. In mice transplanted with HLA-A2⁺ islets, A2-CAR T_reg cells reduced BDC2.5 T cell engraftment, proliferation, and cytokine production and protected mice from diabetes. Islet tolerance was systemic, including protection of the HLA-A2^negative endogenous pancreas. Treated mice remained euglycemic even after removal of the HLA-A2⁺ islet graft and A2-CAR T_reg cells. Thus, A2-CAR T_reg cells can induce linked suppression and long-lasting tolerance to a distinct autoimmune antigen. Tolerance to the autoantigen does not require A2-CAR T_reg persistence, indicating the presence of infectious tolerance. Overall, these data demonstrate that A2-CAR T_reg cells have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation.