title: IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo.
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-10eGFPFoxp3mRFPreporter 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.
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Brockmann
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.|Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gagliani
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Babett
authors.initials: B
authors.lastname: Steglich
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Anastasios D
authors.initials: AD
authors.lastname: Giannou
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Jan
authors.identifier: 0000-0001-8867-5077
authors.initials: J
authors.lastname: Kempski
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Penelope
authors.initials: P
authors.lastname: Pelczar
authors.affiliation: Institut für Transfusionsmedizin, Zentrum für Diagnostik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Geffken
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Bechara
authors.identifier: 0000-0002-8361-5240
authors.initials: B
authors.lastname: Mfarrej
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Francis
authors.initials: F
authors.lastname: Huber
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599.
authors.forename: Yisong Y
authors.initials: YY
authors.lastname: Wan
authors.affiliation: Department of Immunobiology, Yale University, School of Medicine, New Haven, CT 06510.
authors.forename: Enric
authors.initials: E
authors.lastname: Esplugues
authors.affiliation: Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Manuela
authors.identifier: 0000-0003-4535-3152
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany; and.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Krebs
authors.affiliation: Department of Immunobiology, Yale University, School of Medicine, New Haven, CT 06510; richard.flavell@yale.edu shuber@uke.de.|Howard Hughes Medical Institute, Chevy Chase, MD 20815.
authors.forename: Richard A
authors.identifier: 0000-0003-4461-0778
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany; richard.flavell@yale.edu shuber@uke.de.
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
mesh_terms: D000818:Animals; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D053701:Receptors, Interleukin-10 / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases