title: CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer.
abstract: CD4+CD25+ regulatory T cells (Treg) that suppress T cell-mediated immune responses may also regulate other arms of an effective immune response. In particular, in this study we show that Treg directly inhibit NKG2D-mediated NK cell cytotoxicity in vitro and in vivo, effectively suppressing NK cell-mediated tumor rejection. In vitro, Treg were shown to inhibit NKG2D-mediated cytolysis largely by a TGF-beta-dependent mechanism and independently of IL-10. Adoptively transferred Treg suppressed NK cell antimetastatic function in RAG-1-deficient mice. Depletion of Treg before NK cell activation via NKG2D and the activating IL-12 cytokine, dramatically enhanced NK cell-mediated suppression of tumor growth and metastases. Our data illustrate at least one mechanism by which Treg can suppress NK cell antitumor activity and highlight the effectiveness of combining Treg inhibition with subsequent NK cell activation to promote strong innate antitumor immunity.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Australia. mark.smyth@petermac.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Jeremy
authors.initials: J
authors.lastname: Swann
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kyparissoudis
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009368:Neoplasm Transplantation / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D011971:Receptors, Immunologic / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta; D018664:Interleukin-12