title: IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer.
abstract: Foxp3(+)CD4(+) regulatory T (Treg) cells inhibit immune responses and temper inflammation. IL-17(+)CD4(+) T (Th17) cells mediate inflammation of autoimmune diseases. A small population of IL-17(+)Foxp3(+)CD4(+) T cells has been observed in peripheral blood in healthy human beings. However, the biology of IL-17(+)Foxp3(+)CD4(+) T cells remains poorly understood in humans. We investigated their phenotype, cytokine profile, generation, and pathological relevance in patients with ulcerative colitis. We observed that high levels of IL-17(+)Foxp3(+)CD4(+) T cells were selectively accumulated in the colitic microenvironment and associated colon carcinoma. The phenotype and cytokine profile of IL-17(+)Foxp3(+)CD4(+) T cells was overlapping with Th17 and Treg cells. Myeloid APCs, IL-2, and TGF-β are essential for their induction from memory CCR6(+) T cells or Treg cells. IL-17(+)Foxp3(+)CD4(+) T cells functionally suppressed T cell activation and stimulated inflammatory cytokine production in the colitic tissues. Our data indicate that IL-17(+)Foxp3(+) cells may be "inflammatory" Treg cells in the pathological microenvironments. These cells may contribute to the pathogenesis of ulcerative colitis through inducing inflammatory cytokines and inhibiting local T cell immunity, and in turn may mechanistically link human chronic inflammation to tumor development. Our data therefore challenge commonly held beliefs of the anti-inflammatory role of Treg cells and suggest a more complex Treg cell biology, at least in the context of human chronic inflammation and associated carcinoma.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.forename: Ende
authors.initials: E
authors.lastname: Zhao
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.forename: Linhua
authors.initials: L
authors.lastname: Vatan
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.forename: Emina
authors.initials: E
authors.lastname: Huang
authors.forename: Joel
authors.initials: J
authors.lastname: Greenson
authors.forename: Alfred
authors.initials: A
authors.lastname: Chang
authors.forename: Jacek
authors.initials: J
authors.lastname: Roliński
authors.forename: Piotr
authors.initials: P
authors.lastname: Radwan
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fang
authors.forename: Guobin
authors.initials: G
authors.lastname: Wang
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D018920:Coculture Techniques; D003093:Colitis, Ulcerative / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006131:Growth Inhibitors; C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17