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

被引：135

作者：

Perez, Laura Garcia ^{[1
]}

Kempski, Jan ^{[1
]}

McGee, Heather M. ^{[2
]}

Pelzcar, Penelope ^{[1
]}

Agalioti, Theodora ^{[3
]}

Giannou, Anastasios ^{[1
]}

Konczalla, Leonie ^{[3
]}

Brockmann, Leonie ^{[4
]}

Wahib, Ramez ^{[3
]}

Xu, Hao ^{[5
]}

Vesely, Maria Carolina Amezcua ^{[5
]}

Soukou, Shiwa ^{[1
]}

Steglich, Babett ^{[1
,3
]}

Bedke, Tanja ^{[1
]}

Manthey, Carolin ^{[1
]}

Seiz, Oliver ^{[1
]}

Diercks, Bjoern-Philipp ^{[6
]}

Gnafakis, Stylianos ^{[7
,8
,9
]}

Guse, Andreas H. ^{[6
]}

Perez, Daniel ^{[3
]}

Izbicki, Jakob R. ^{[3
]}

Gagliani, Nicola ^{[1
,3
,10
]}

Flavell, Richard A. ^{[5
,11
]}

Huber, Samuel ^{[1
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Dept Med, D-20246 Hamburg, Germany

[2] Salk Inst Biol Studies, Ctr Immunobiol & Microbial Pathogenesis, La Jolla, CA 10010 USA

[3] Univ Med Ctr Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, D-20246 Hamburg, Germany

[4] Columbia Univ, Dept Microbiol & Immunol, New York, NY USA

[5] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA

[6] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, D-20246 Hamburg, Germany

[7] Charite Univ Med Berlin, Dept Microbiol Infect Dis & Immunol, Lab Innate Immun, Hindenburgdamm 30, D-12203 Berlin, Germany

[8] BIH, Anna Louisa Karsch Str 2, D-10117 Berlin, Germany

[9] Deutsch Rheuma Forschungszentrum, Mucosal & Dev Immunol, Charitepl 1, D-10117 Berlin, Germany

[10] Karolinska Inst & Univ Hosp, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden

[11] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

ARYL-HYDROCARBON RECEPTOR; GROWTH-FACTOR-BETA; T-CELLS; COLORECTAL-CANCER; TH22; CELLS; INTERLEUKIN (IL)-22; CUTTING EDGE; T(H)17 CELLS; DIFFERENTIATION; EXPRESSION;

D O I：

10.1038/s41467-020-16363-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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