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

IL-10 is essential to maintain intestinal homeostasis. CD4⁺ T regulatory type 1 (T_R1) 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_R1 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_R1 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_R1 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_R1 cells, currently employed for cell therapy, to confirm our results. We found that murine T_R1 cells expressed functional IL-10Rα. T_R1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. T_R1 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_R1 cells. In conclusion, T_R1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that to optimize T_R1 cell-based therapy, IL-10 receptor expression has to be taken into consideration.