IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3− effector T cells

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Abstract
Foxp3 is required for the generation and function of regulatory T cells. Kuchroo and colleagues find that interleukin 4 blocks the generation of these cells but promotes T helper cells that produce interleukins 9 and 10. Transcription factor Foxp3 is critical for generating regulatory T cells (Treg cells). Transforming growth factor-β (TGF-β) induces Foxp3 and suppressive Treg cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible Treg cells. Here we show that IL-4 blocked the generation of TGF-β-induced Foxp3+ Treg cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9+IL-10+ T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9+IL-10+ T cells into recombination-activating gene 1–deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9+IL-10+ T cells were transferred with CD45RBhi CD4+ effector T cells. Thus IL-9+IL-10+ T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.