title: Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis.
abstract: Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) 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 IL17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote enterotoxigenic Bacteroides fragilis (ETBF). Depletion of Tregs in ETBF-colonized C57BL/6 FOXP3(DTR) mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL17 to IFNγ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL17 inflammation and was independent of IFNγ. Treg enhancement of IL17 production is cell-extrinsic. IL2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL2 in the local microenvironment, allowing the Th17 development necessary to promote ETBF-triggered neoplasia, and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis.
  
  
  CONCLUSIONS
  Tregs promote an oncogenic immune response to a common human symbiote associated with inflammatory bowel disease and colorectal cancer. Our data define mechanisms by which mucosal Tregs, despite suppressing excessive inflammation, promote the earliest stages of immune procarcinogenesis via enhancement of IL17 production at the expense of IFNγ production.
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Geis
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hongni
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xinqun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Division of Pediatric Gastroenterology, Children's National Medical Center, George Washington University School of Medicine, Washington, DC.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Wolfe
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. fhousse1@jhmi.edu.
authors.forename: Franck
authors.initials: F
authors.lastname: Housseau
mesh_terms: D000818:Animals; D001442:Bacteroides Infections / Q000150:complications* / Q000382:microbiology; D001441:Bacteroides fragilis / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D007376:Interleukin-2