title: Human CCR4+ CCR6+ Th17 cells suppress autologous CD8+ T cell responses.
abstract: The role of Th17 cells in cancer patients remains unclear and controversial. In this study, we have analyzed the phenotype of in vitro primed Th17 cells and further characterized their function on the basis of CCR4 and CCR6 expression. We show a novel function for a subset of IL-17-secreting CD4(+) T cells, namely, CCR4(+)CCR6(+)Th17 cells. When cultured together, CCR4(+)CCR6(+)Th17 cells suppressed the lytic function, proliferation, and cytokine secretion of both Ag-specific and CD3/CD28/CD2-stimulated autologous CD8(+) T cells. In contrast, CCR4(-)CCR6(+) CD4(+) T cells, which also secrete IL-17, did not affect the CD8(+) T cells. Suppression of CD8(+) T cells by CCR4(+)CCR6(+)Th17 cells was partially dependent on TGF-β, because neutralization of TGF-β in cocultures reversed their suppressor function. In addition, we also found an increase in the frequency of CCR4(+)CCR6(+), but not CCR4(-)CCR6(+) Th17 cells in peripheral blood of hepatocellular carcinoma patients. Our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in hepatocellular carcinoma. This has important implications when studying the mechanisms of carcinogenesis, as well as designing effective immunotherapy protocols for patients with cancer.
authors.affiliation: Gastrointestinal Malignancy Section, Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Bastian
authors.initials: B
authors.lastname: Hoechst
authors.forename: Jaba
authors.initials: J
authors.lastname: Gamrekelashvili
authors.forename: Lars A
authors.initials: LA
authors.lastname: Ormandy
authors.forename: Torsten
authors.initials: T
authors.lastname: Voigtländer
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.forename: Kris
authors.initials: K
authors.lastname: Ylaya
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Korangy
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000276:immunology*; D054398:Receptors, CCR4 / Q000276:immunology / Q000378:metabolism; D054399:Receptors, CCR6 / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology
chemical_list: C515354:CCR4 protein, human; C106311:CCR6 protein, human; D016207:Cytokines; D054398:Receptors, CCR4; D054399:Receptors, CCR6