Oliver Seiz, Nicola Gagliani, Carolin F. Manthey, Jan Kempski, Anastasios D. Giannou, Penelope Pelzcar, Jakob R. Izbicki, Babett Steglich, Ramez Wahib, Daniel Perez, Stylianos Gnafakis, Shiwa Soukou, Leonie Brockmann, Tanja Bedke, Andreas H. Guse, Samuel Huber, Hao Xu, Laura Garcia Perez, Theodora Agalioti, Richard A. Flavell, Heather M. McGee, Björn-Philipp Diercks, Leonie Konczalla, and Maria Carolina Amezcua Vesely
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-β1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-β 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-β1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-β 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-β signaling. We show that TGF-β, 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-β, enriched in patients with colorectal cancer (CRC) and drive CRC progression in mice.