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Nat Commun. 2018 Jul 20;9(1):2858. doi: 10.1038/s41467-018-05167-8.

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

Author information

1
Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93053, Germany.
2
Miltenyi Biotec GmbH, Friedrich-Ebert-Str. 68, 51429, Bergisch Gladbach, Germany.
3
Transfusion Medicine, Institute for Clinical Chemistry, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
4
Department of Gynecology and Obstetrics, University Medical Center Regensburg, Landshuter Straße 65, 93053, Regensburg, Germany.
5
Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
6
Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Am BioPark 9, 93053, Regensburg, Germany.
7
Department of Surgery, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24015, Kiel, Germany.
8
Institute for Virology and Immunobiology, University of Würzburg, Versbacher Str. 7, 97078, Würzburg, Germany.
9
Institute for Medical Immunology, Berlin Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
10
Inmunología de Trasplantes, Centro Nacional de Microbiología, Cta. Majadahonda-Pozuelo Km 2, 28220, Madrid, Spain.
11
Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93053, Germany. james.hutchinson@klinik.uni-regensburg.de.

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.

PMID:
30030423
PMCID:
PMC6054648
DOI:
10.1038/s41467-018-05167-8
[Indexed for MEDLINE]
Free PMC Article

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