IL-9 induces differentiation of T H 17 cells and enhances function of FoxP3 + natural regulatory T cells

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Abstract
The development of T helper (T H )17 and regulatory T (T reg ) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-β alone induces FoxP3 + T reg cells, but together with IL-6 or IL-21 induces T H 17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of T H 17 cells and T reg function. IL-9 predominantly produced by T H 17 cells, synergizes with TGF-β1 to differentiate naïve CD4 + T cells into T H 17 cells, while IL-9 secretion by T H 17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3 + CD4 + T reg cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nT regs in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on T H 17 and T regs is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses.