TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer
Laura García Pérez, Jan Kempski, Heather M. McGee, Penelope Pelzcar, Theodora Agalioti, Anastasios D. Giannou, Leonie Konczalla, Leonie Brockmann, Ramez Wahib, Hao Xu, María Carolina Amezcua Vesely, Shiwa Soukou, Babett Steglich, Tanja Bedke, Carolin Manthey, Oliver Seiz, Björn‐Philipp Diercks, Stylianos Gnafakis, Andreas H. Guse, Daniel Pérez, Jakob R. Izbicki, Nicola Gagliani, Richard A. Flavell, Samuel Huber
Abstract
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.