Cell therapy with human interleukin 10-producing ILC2s enhances islet function and inhibits allograft rejection

Group 2 innate lymphoid cells (ILC2s) that produce interleukin (IL)-10 (IL-10⁺ILC2s) have demonstrated regulatory and tissue-protective properties in murine studies, but preclinical studies are lacking that explore the potential of human IL-10⁺ILC2s as a tolerance-promoting cell therapy for transplantation or autoimmunity. Here, we investigated whether human IL-10⁺ILC2s could enhance islet function and prevent allograft rejection in humanized mouse models of islet transplantation. In vitro, human IL-10⁺ILC2s did not display cytotoxicity toward allogeneic deceased-donor islets or stem cell-derived islet-like cells, and co-transplantation with IL-10⁺ILC2s significantly improved glucose control post-transplantation. Allogeneic IL10⁺ILC2s directly inhibited T cell-mediated cytotoxicity against islet-like cells in vitro and, in an antigen-specific transplant rejection model, prevented T cell-mediated rejection of deceased-donor islet grafts. Effects were greater with allogeneic IL-10⁺ILC2s, as autologous cells did not inhibit T cell interferon-γ production or cytotoxic activity in vitro and were not sufficient to prevent islet rejection in vivo. Collectively, these studies provide proof-of-principle that human IL-10⁺ILC2s have therapeutic potential for islet transplantation and type 1 diabetes and support their use as an allogeneic regulatory cell therapy.