Group 2 Innate lymphoid cells promote allograft survival by constraining and inducing anergy in alloreactive CD4+ T cells

Despite significant improvements in solid organ transplant outcomes over the past several decades, our limited understanding of the immune interface between donor organs and recipient immune systems has hindered the development of strategies to expand immunoregulatory cell populations and induce immune tolerance in transplant recipients. Given that group 2 innate lymphoid cells (ILC2s) are resident in transplanted solid organs, play a role in wound healing, and coordinate immunoregulatory cell populations, we sought to investigate their function in the alloimmune response. Using a murine heterotopic cardiac transplant model, we demonstrate that recipient ILC2s replace donor ILC2s and upregulate MHC class II (MHCII) without expressing costimulatory molecules. These recipient-derived ILC2s process and present alloantigens, inducing CD4+ T cell anergy through the Caspase-3-dependent pathway. In the absence of recipient-derived ILC2s, we observed a marked increase in infiltrating donor-reactive CD4+ T cells and significantly reduced allograft survival. Furthermore, in vivo expansion of ILC2s via IL-33 administration prolonged murine heart allograft survival. Collectively, these findings reveal a critical and previously unrecognized immunoregulatory role of host-derived ILC2s in solid organ transplantation, where they promote alloimmune tolerance by inducing anergy in alloreactive CD4+ T cells.