EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be found. Here we identified that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in Th cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that AREG-EGFR signaling induces HIF1α, which binds and transactivates IL-9, IRF4 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppress their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression. RNASeq analysis of Th9 cells from WT and Areg-/- mice.