Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05167-8
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Funding
- European Union 7th Framework Programme through The ONE Study initiative [260687]
- Deutsche Forschungsgemeinsafcht [HU 1838/1-1, HU 1838/21]
- EU
- Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies (A FACTT) consortium - European Union Horizon 2020 programme
- Regensburg Center for Interventional Immunology
- UKR
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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-beta, 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.
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