TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity.

Human regulatory macrophages (Mreg) have shown early clinical promise as a cell-based adjunct immunosuppressive therapy in solid organ transplantation. It is hypothesised that recipient CD4+ T cell responses are actively regulated through direct allorecognition of donor-derived Mregs. Here we show that human Mregs convert allogeneic CD4+ T cells to IL-10-producing, TIGIT+ FoxP3+-induced regulatory T cells that non-specifically suppress bystander T cells and inhibit dendritic cell maturation. Differentiation of Mreg-induced Tregs relies on multiple non-redundant mechanisms that are not exclusive to interaction of Mregs and T cells, including signals mediated by indoleamine 2,3-dioxygenase, TGF-β, retinoic acid, Notch and progestagen-associated endometrial protein. Preoperative administration of donor-derived Mregs to living-donor kidney transplant recipients results in an acute increase in circulating TIGIT+ Tregs. These results suggest a feed-forward mechanism by which Mreg treatment promotes allograft acceptance through rapid induction of direct-pathway Tregs.The authors gratefully acknowledge the support of the European Union 7th Framework Programme through The ONE Study initiative (award 260687). This work was also partly funded by the Deutsche Forschungsgemeinschaft (awards HU 1838/1-1 and HU 1838/2-1), the EU-funded Reprogramming the Immune System for Establishment of Tolerance (RISET) network, the Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies (A FACTT) consortium funded by the European Union Horizon 2020 programme and the Regensburg Center for Interventional Immunology. L.W. received an intramural (ReForM-A) award from UKR.S