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The journal of immunology : official journal of the American Association of Immunologists v.198 no.3, 2017년, pp.1130 - 1141   SCI SCIE
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IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo

Brockmann, Leonie ; Gagliani, Nicola ; Steglich, Babett ; Giannou, Anastasios D. ; Kempski, Jan ; Pelczar, Penelope ; Geffken, Maria ; Mfarrej, Bechara ; Huber, Francis ; Herkel, Johannes ; Wan, Yisong Y. ; Esplugues, Enric ; Battaglia, Manuela ; Krebs, Christian F. ; Flavell, Richard A. ; Huber, Samuel ;
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    IL-10 is essential to maintain intestinal homeostasis. CD4 + T regulatory type 1 (T R 1) 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 T R 1 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 T R 1 cells in vivo. Double IL-10 eGFP Foxp3 mRFP reporter mice and transgenic mice with impairment in IL-10 receptor signaling were used to test the activity of T R 1 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 T R 1 cells, currently employed for cell therapy, to confirm our results. We found that murine T R 1 cells expressed functional IL-10Rα. T R 1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. T R 1 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 T R 1 cells. In conclusion, T R 1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that to optimize T R 1 cell–based therapy, IL-10 receptor expression has to be taken into consideration.


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