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

TY - JOUR

T1 - IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo

AU - Brockmann, Leonie

AU - Gagliani, Nicola

AU - Steglich, Babett

AU - Giannou, Anastasios D

AU - Kempski, Jan

AU - Pelczar, Penelope

AU - Geffken, Maria

AU - Mfarrej, Bechara

AU - Huber, Francis

AU - Herkel, Johannes

AU - Wan, Yisong Y

AU - Esplugues, Enric

AU - Battaglia, Manuela

AU - Krebs, Christian F

AU - Flavell, Richard A

AU - Huber, Samuel

N1 - Copyright © 2016 by The American Association of Immunologists, Inc.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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-10(eGFP) Foxp3(mRFP) 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.

AB - 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-10(eGFP) Foxp3(mRFP) 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.

U2 - 10.4049/jimmunol.1601045

DO - 10.4049/jimmunol.1601045

M3 - SCORING: Journal article

C2 - 28003377

VL - 198

SP - 1130

EP - 1141

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 3

ER -