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

Regulatory T cells (Treg 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 Treg cells can limit anti-HLA-A2 alloimmunity. However, it was unknown whether A2-CAR Treg 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 Treg cells could control hyperglycemia induced by diabetogenic BDC2.5 effector T cells. In mice transplanted with HLA-A2+ islets, A2-CAR Treg 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-A2negative endogenous pancreas. Treated mice remained euglycemic even after removal of the HLA-A2+ islet graft and A2-CAR Treg cells. Thus, A2-CAR Treg cells can induce linked suppression and long-lasting tolerance to a distinct autoimmune antigen. Tolerance to the autoantigen does not require A2-CAR Treg persistence, indicating the presence of infectious tolerance. Overall, these data demonstrate that A2-CAR Treg cells have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation.