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

ABSTRACT: 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-? 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-? signaling. When TGF-? was replaced by IL-1?, the combination of IL-1? and IL-4 efficiently promoted IL-9-producing T cells (Th9^IL-4+IL-1?). Th9^{IL-4+ IL-1?} cells are phenotypically distinct T cells compared to classic Th9 cells (Th9^IL-4+TGF-?) and other Th cells, and are enriched for IL-1 and NF-?B gene signatures. Inhibition of NF-?B but not TGF-?-signaling negates IL-9 production by Th9^IL-4+IL-1? cells. Furthermore, when compared with classic Th9^IL-4+TGF-? cells, Th9^IL-4+IL-1? 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.

SUBMITTER: Xue G 

PROVIDER: S-EPMC6435687 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature