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J Immunol. 2017 Feb 1;198(3):1130-1141. doi: 10.4049/jimmunol.1601045. Epub 2016 Dec 21.

IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo.

Author information

1
I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
2
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
3
Institut für Transfusionsmedizin, Zentrum für Diagnostik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
4
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
5
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599.
6
Department of Immunobiology, Yale University, School of Medicine, New Haven, CT 06510.
7
III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany; and.
8
Department of Immunobiology, Yale University, School of Medicine, New Haven, CT 06510; richard.flavell@yale.edu shuber@uke.de.
9
Howard Hughes Medical Institute, Chevy Chase, MD 20815.
10
I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany; richard.flavell@yale.edu shuber@uke.de.

Abstract

IL-10 is essential to maintain intestinal homeostasis. CD4+ T regulatory type 1 (TR1) cells produce large amounts of this cytokine and are therefore currently being examined in clinical trials as T cell therapy in patients with inflammatory bowel disease. However, factors and molecular signals sustaining TR1 cell regulatory activity still need to be identified to optimize the efficiency and ensure the safety of these trials. We investigated the role of IL-10 signaling in mature TR1 cells in vivo. Double IL-10eGFP Foxp3mRFP reporter mice and transgenic mice with impairment in IL-10 receptor signaling were used to test the activity of TR1 cells in a murine inflammatory bowel disease model, a model that resembles the trials performed in humans. The molecular signaling was elucidated in vitro. Finally, we used human TR1 cells, currently employed for cell therapy, to confirm our results. We found that murine TR1 cells expressed functional IL-10Rα. TR1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. TR1 cells required IL-10 receptor signaling to activate p38 MAPK, thereby sustaining IL-10 production, which ultimately mediated their suppressive activity. Finally, we confirmed these data using human TR1 cells. In conclusion, TR1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that to optimize TR1 cell-based therapy, IL-10 receptor expression has to be taken into consideration.

PMID:
28003377
PMCID:
PMC5263184
DOI:
10.4049/jimmunol.1601045
[Indexed for MEDLINE]
Free PMC Article

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