Transcription factors in the development of Th9 cells

Abstract

Cytokines are extracellular proteins that mediate communication between cells. T helper cell subsets secrete specific cytokines that promote the development of inflammation. Naïve CD4+ T cells activated and primed in the presence of TGF-β and IL-4 predominantly secrete IL-9, a cytokine that acts as a growth factor for T cells and mast cells, and promotes allergic inflammation. The transcription factors downstream of TGF-β- and IL-4-induced signaling, and that are required for expression of IL-9, have not been previously examined. IL-4 signaling induces the expression of IRF4, a transcription factor required for the development of Th9 cells. IL-4 and the downstream-activated factor STAT6 also interfere with the expression of the transcription factors T-bet and Foxp3 that inhibit IL-9 production from Th9 cells. The TGF-β pathway induces the expression of PU.1, another transcription factor required for Th9 development. In the absence of PU.1 there is increased association of a subset of histone deacetylases to the Il9 promoter. In developing Th9 cells, PU.1 can bind to the Il9 promoter and recruit specific histone acetyltransferases, including Gcn5 to the Il9 gene. Gcn5 functionally contributes to Il9 expression as IL-9 production is diminished when Gcn5 expression is reduced, although other cytokines expressed by Th9 cells are not affected. While Gcn5 is not required for PU.1 or IRF4 binding to Il9, it is important for controlling histone acetylation at the Il9 gene promoter. Together these data define the STAT6-dependent transcription factor network in Th9 cells and the mechanism of PU.1-dependent IL-9 induction in Th9 cells and might indicate that targeting IL-9 regulation is a viable approach for treating inflammatory disease.