IL‐33‐activated murine mast cells control the dichotomy between RORγt+ and Helios+ Tregs via the MK2/3‐mediated IL‐6 production in vitro

In mast cells, IL‐33 typically induces the activation of NF‐κB, which results in the production of cytokines such as IL‐6 and IL‐2. Here, we demonstrate that the IL‐33‐induced IL‐6 production in murine mast cells and the formation of RORγt⁺ T_regs essentially depends on the MAPKAPs, MK2, and MK3 (MK2/3) downstream of MyD88. In contrast to this, the IL‐33‐induced and MyD88‐dependent IL‐2 production in mast cells contributes to the maintenance of Helios⁺ T_regs. Thereby, the IL‐33‐induced IL‐2 response and, thus, the maintenance of Helios⁺ T_regs are limited by an IL‐6‐mediated autocrine negative feedback stimulation acting on mast cells. Collectively, we present MK2/3 in IL‐33‐activated mast cells as a signaling node, which controls the dichotomy between RORγt⁺ T_reg and Helios⁺ T_reg in vitro.