Interleukin 4 inhibits TGF-β-induced-Foxp3(+)T cells and generates, in combination with TGF-β, Foxp3(−) effector T cells that produce interleukins 9 and 10

Foxp3 is a key transcription factor involved in the generation and function of regulatory T (T(reg)) cells. Transforming growth factor β (TGF-β) induces Foxp3, which generates inducible Foxp3(+) T(reg) cells from naïve T cells, and interleukin 6 (IL-6) inhibits the generation of inducible T(reg) cells and induces T helper cells that produce IL-17 (T(H)-17 cells). However, a role for IL-4 in the generation of TGF-β-induced T(reg) cells and/or the generation of effector CD4(+) T helper cells has not been studied. Here, we show that IL-4 blocked the generation of TGF-β-induced Foxp3(+) T(reg) cells. Instead, IL-4 induced a population of T helper cells that predominantly produce IL-9 and IL-10. The IL-9(+)IL-10(+) T cells did not exhibit any regulatory properties in spite of producing large quantities of IL-10. Adoptive transfer of IL-9(+)IL-10(+)producing T cells into RAG-1-deficient mice induced colitis and peripheral neuritis. Interestingly, the severity of tissue inflammation was aggravated when IL-9(+)IL-10(+) T cells were co-transferred with CD45RB(hi) CD4(+) effector T cells into RAG-1-deficient mice, which indicated that IL-9(+)IL-10(+) T cells do not display any suppressive function and therefore constitute a unique population of IL-10-producing helper-effector T cells that promote tissue inflammation.