Activin A Promotes Differentiation of a Pathogenic Multicytokine IL-9-secreting CD4+ T Cell Population

The development of Th subsets results from cellular and cytokine cues that are present in the inflammatory environment. The developing T cell integrates multiple signals from the environment that sculpt the cytokine-producing capacity of the effector T cell. Importantly, T cells can discriminate similar cytokine signals to generate distinct outcomes, and that discrimination is critical in Th subset development. IL-9-secreting Th9 cells regulate multiple immune responses, including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. In combination with IL-4, TGF-β or activin A promotes IL-9 production; yet, it is not clear if both TGF-β family members generate Th9 cells with identical phenotype and function. We observed that in contrast to TGF-β that efficiently represses Th2 cytokines in murine Th9 cultures, differentiation with activin A produced a multicytokine T cell phenotype with secretion of IL-4, IL-5, IL-13, and IL-10 in addition to IL-9. Moreover, multicytokine secreting cells are more effective at promoting allergic inflammation. These observations suggest that although TGF-β and IL-4 were identified as cytokines that stimulate optimal IL-9 production, they might not be the only cytokines that generate optimal function from IL-9-producing T cells in immunity and disease.