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

TGF-β and IL-4 were recently shown to selectively upregulate IL-9 production by naïve CD4(+) T cells. We report here that TGF-β interactions with IL-1α, IL-1β, 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-β. 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-β/IL-1 and TGF-β/IL-4 as the main control points of IL-9 synthesis.