TGF-β interactions with IL-1 family members trigger IL-4-independent IL-9 production by mouse CD4+ T cells

TGF-beta and IL-4 were recently shown to selectively upregulate IL-9 production by nave CDC+ T cells. We report here that TGF-beta interactions with IL-1 alpha, IL-1 beta, IL-18, and IL-33 have equivalent IL-9-stimulating activities that function even in IL-4-deficient animals. This was observed after in vitro antigenic stimulation of immunized or unprimed mice and after polyclonal T-cell activation. Based on intracellular IL-9 staining, all IL-9-producing cells were CD4(+) and 80-90% had proliferated, as indicated by reduced CFSE staining. In contrast to IL-9, IL-13 and IL-17 were strongly stimulated by IL-1 and either inhibited (IL-13) or were unaffected (IL-17) by addition of TGF-beta. IL-9 and IL-17 production also differed in their dependence on IL-2 and regulation by IL-1/IL-23. As IL-9 levels were much lower in Th2 and Th17 cultures, our results identify TGF-beta/IL-1 and TGF-beta/IL-4 as the main control points of IL-9 synthesis.