IL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling

IL-9-producing CD4(+) (Th9) cells are a subset of CD4(+) T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-beta have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-beta signaling. When TGF-beta was replaced by IL-1 beta, the combination of IL-1 beta and IL-4 efficiently promoted IL-9-producing T cells (Th9(IL-4+IL-1 beta)). Th9(IL-4+IL-1 beta) cells are phenotypically distinct T cells compared to classic Th9 cells (Th9(IL-4+TGF-beta)) and other Th cells, and are enriched for IL-1 and NF-kappa B gene signatures. Inhibition of NF-kappa B but not TGF-beta-signaling negates IL-9 production by Th9(IL-4+IL-1 beta) cells. Furthermore, when compared with classic Th9(IL-4+TGF-beta) cells, Th9(IL-4+IL-1 beta) cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies.