TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer

IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-beta 1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-beta signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-beta 1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-beta signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-beta signaling. We show that TGF-beta, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells. Poly-functional helper T cells can have a stronger effect than mono-functional T cells, but whether the response is qualitatively different is not clear. Here the authors show that a population of IL-17(+)IL-22(+), but not single IL-22(+), CD4(+) T cells are induced by TGF-beta, enriched in patients with colorectal cancer (CRC) and drive CRC progression in mice.