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

• Published in: Nature communications Vol. 11; no. 1; pp. 2608 - 14
• Main Authors: Perez, Laura Garcia, Kempski, Jan, McGee, Heather M., Pelzcar, Penelope, Agalioti, Theodora, Giannou, Anastasios, Konczalla, Leonie, Brockmann, Leonie, Wahib, Ramez, Xu, Hao, Vesely, Maria Carolina Amezcua, Soukou, Shiwa, Steglich, Babett, Bedke, Tanja, Manthey, Carolin, Seiz, Oliver, Diercks, Björn-Philipp, Gnafakis, Stylianos, Guse, Andreas H., Perez, Daniel, Izbicki, Jakob R., Gagliani, Nicola, Flavell, Richard A., Huber, Samuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 13/21; 13/31; 38; 38/88; 59; 631/250/1619/554/1898; 631/250/2152/1566/2493; 64; 64/60; 692/4028/67/580; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Carcinogenesis - immunology; CD4 antigen; Cell Differentiation; Colitis; Colitis - complications; Colitis - immunology; Colon; Colon cancer; Colonic Neoplasms - etiology; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - etiology; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Disease Models, Animal; Female; Genotoxicity; Helper cells; Humanities and Social Sciences; Humans; Interleukin 17; Interleukin 22; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukins - biosynthesis; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Phosphatidylinositol 3-Kinases - metabolism; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Science; Science (multidisciplinary); Signal Transduction - immunology; Signaling; Th17 Cells - immunology; Th17 Cells - pathology; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16363-w

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.