title: Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity.
abstract: OBJECTIVE
  Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment.
  
  
  METHODS
  Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4+ effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function.
  
  
  RESULTS
  We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4+ effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-γ production of TH1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1α in the modulation of CD4+ T cell functions under hypoxic conditions.
  
  
  CONCLUSIONS
  Our data indicate that oxygen availability can function as a local modulator of CD4+ T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer.
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Skibbe
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Adamczyk
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.affiliation: Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Pastille
authors.affiliation: Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D015687:Cell Hypoxia / Q000276:immunology; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology; D007108:Immune Tolerance; D007157:Immunologic Surveillance; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000611649:IFNG protein, mouse; D007371:Interferon-gamma
keywords: Colitis-associated colon cancer; HIF-1a; Hypoxia; T cell function