Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis.
Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis.
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DOI：
10.1158/2159-8290.cd-15-0447
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发表时间：
2015-10
期刊：
影响因子：
28.2
通讯作者：
Housseau F
中科院分区：
文献类型：
--
作者：
Geis AL;Fan H;Wu X;Wu S;Huso DL;Wolfe JL;Sears CL;Pardoll DM;Housseau F
Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are pro-carcinogenic are not fully understood. Tregs typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL-17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote ETBF. Depletion of Tregs in ETBF-colonized C57BL/6 Foxp3DTR mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL-17 to IFN-γ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL-17 inflammation and IFN-γ-independent. Treg enhancement of IL-17 production is cell-extrinsic. IL-2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL-2 in the local microenvironment, allowing Th17 development necessary to promote ETBF-triggered neoplasia and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis.
