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

Paloma Riquelme, Jan Haarer, Anja Kammler, Lisa Walter, Stefan Tomiuk, Norbert Ahrens, Anja K. Wege, Ivan Goecze, Daniel Zecher, Bernhard Banas, Rainer Spang, Fred Fändrich, Manfred B. Lutz, Birgit Sawitzki, Hans J. Schlitt, Jordi Ochando, Edward K. Geissler and James A. Hutchinson ()
Additional contact information
Paloma Riquelme: University Hospital Regensburg
Jan Haarer: University Hospital Regensburg
Anja Kammler: University Hospital Regensburg
Lisa Walter: University Hospital Regensburg
Stefan Tomiuk: Miltenyi Biotec GmbH
Norbert Ahrens: University Hospital Regensburg
Anja K. Wege: University Medical Center Regensburg
Ivan Goecze: University Hospital Regensburg
Daniel Zecher: University Hospital Regensburg
Bernhard Banas: University Hospital Regensburg
Rainer Spang: University of Regensburg
Fred Fändrich: University Hospital Schleswig-Holstein
Manfred B. Lutz: University of Würzburg
Birgit Sawitzki: Berlin Charité University Hospital
Hans J. Schlitt: University Hospital Regensburg
Jordi Ochando: Centro Nacional de Microbiología
Edward K. Geissler: University Hospital Regensburg
James A. Hutchinson: University Hospital Regensburg

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05167-8

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