title: CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.
abstract: Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell-mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)-beta, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-beta-/- T reg cells into nude mice suppressed NK cell-mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell-mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.
authors.affiliation: ERM 0208, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris XI, France.
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Cédric
authors.initials: C
authors.lastname: Ménard
authors.forename: Magali
authors.initials: M
authors.lastname: Terme
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Julien
authors.initials: J
authors.lastname: Taieb
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Pierre E
authors.initials: PE
authors.lastname: Puig
authors.forename: Sophie
authors.initials: S
authors.lastname: Novault
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Axel
authors.initials: A
authors.lastname: Lecesne
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Jacky
authors.initials: J
authors.lastname: Bernard
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
authors.forename: Antonio
authors.initials: A
authors.lastname: Freitas
authors.forename: Thomas
authors.initials: T
authors.lastname: Tursz
authors.forename: Orianne
authors.initials: O
authors.lastname: Wagner-Ballon
authors.forename: Claude
authors.initials: C
authors.lastname: Capron
authors.forename: William
authors.initials: W
authors.lastname: Vainchencker
authors.forename: François
authors.initials: F
authors.lastname: Martin
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D005602:France; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta