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bioRxiv · 10.1101/2024.04.06.588414

CAR Tregs mediate linked suppression and infectious tolerance in islet transplantation

Wardell, C.·Fung, V.·Chen, E.·Haque, M.·Gillies, J.·Spanier, J.·Mojibian, M.·Fife, B. T.·Levings, M. K.
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Abstract

Regulatory T cells (Tregs) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using an HLA-A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR Tregs limited anti-HLA-A2 alloimmunity. However, it was unknown if A2-CAR Tregs could also limit immunity to autoantigens. Using a model of HLA-A2+ islet transplantation into immunodeficient non-obese diabetic mice, we investigated if A2-CAR Tregs could control diabetes induced by islet-autoreactive (BDC2.5) T cells. In mice transplanted with HLA-A2+ islets, A2-CAR Tregs reduced BDC2.5 T cell engraftment, proliferation and cytokine production, and protected mice from diabetes. Tolerance to islets was systemic, including protection of the HLA-A2negative endogenous pancreas. In tolerant mice, a significant proportion of BDC2.5 T cells gained FOXP3 expression suggesting that long-term tolerance is maintained by de novo Treg generation. Thus, A2-CAR Tregs mediate linked suppression and infectious tolerance and have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation. One Sentence SummaryAlloreactive chimeric antigen receptor-engineered regulatory T cells limit diabetogenic T cell engraftment and function to prevent type 1 diabetes.

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Wardell, C., Fung, V., Chen, E., Haque, M., Gillies, J., Spanier, J., Mojibian, M., Fife, B. T., Levings, M. K.. 2024-04-10. CAR Tregs mediate linked suppression and infectious tolerance in islet transplantation. https://doi.org/10.1101/2024.04.06.588414

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