IL‐3 is essential for ICOS‐L stabilization on mast cells, and sustains the IL‐33‐induced RORγt(+) T(reg) generation via enhanced IL‐6 induction

IL‐33 is a member of the IL‐1 family. By binding to its receptor ST2 (IL‐33R) on mast cells, IL‐33 induces the MyD88‐dependent activation of the TAK1‐IKK2 signalling module resulting in activation of the MAP kinases p38, JNK1/2 and ERK1/2, and of NFκB. Depending on the kinases activated in these pathways, the IL‐33‐induced signalling is essential for production of IL‐6 or IL‐2. This was shown to control the dichotomy between RORγt(+) and Helios(+) T(regs), respectively. SCF, the ligand of c‐Kit (CD117), can enhance these effects. Here, we show that IL‐3, another growth factor for mast cells, is essential for the expression of ICOS‐L on BMMCs, and costimulation with IL‐3 potentiated the IL‐33‐induced IL‐6 production similar to SCF. In contrast to the enhanced IL‐2 production by SCF‐induced modulation of the IL‐33 signalling, IL‐3 blocked the production of IL‐2. Consequently, IL‐3 shifted the IL‐33‐induced T(reg) dichotomy towards RORγt(+) T(regs) at the expense of RORγt(−) Helios(+) T(regs). However, ICOS‐L expression was downregulated by IL‐33. In line with that, ICOS‐L did not play any important role in the T(reg) modulation by IL‐3/IL‐33‐activated mast cells. These findings demonstrate that different from the mast cell growth factor SCF, IL‐3 can alter the IL‐33‐induced and mast cell‐dependent regulation of T(reg) subpopulations by modulating mast cell‐derived cytokine profiles.