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(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(mRF)P 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-10R alpha. 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.