CAR T <sub>reg</sub> cells mediate linked suppression and infectious tolerance in islet transplantation in mice
Christine M. Wardell, Vivian Fung, Eleanor Y. Chen, Manjurul Haque, David F. H. Tan, Monica Leca, Jana Gillies, Justin A. Spanier, Majid Mojibian, Brian T. Fife, Megan K. Levings
Abstract
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.