Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis
2015
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.
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