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¹ ERM 0208, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris XI
² Unité d'Immunothérapie, U362, Institut Gustave Roussy, 94805 Villejuif, France
³ Department of Medical Oncology, U362, Institut Gustave Roussy, 94805 Villejuif, France
⁴ INSERM, U362, Institut Gustave Roussy, 94805 Villejuif, France
⁵ INSERM, U517, Faculté de Médecine, University of Burgundy, 21079 Dijon, France
⁶ Centre d'Immunologie, INSERM/Centre National de la Recherche Scientifique de Marseille Luminy, 13288 Marseille, France
⁷ Hospices Civils de Lyon, Hôpital Edouard Hériot, 69003 Lyon, France
⁸ Centre Jean Godineau, Etablissement Français du Sang, 51056 Reims, France
⁹ INSERM, U561, Hôpital Saint Vincent de Paul, Assistance Publique-Hôpitaux de Paris, 75674 Paris, France
¹⁰ Unité Biologie des Populations Lymphocytaires, Centre National de la Recherche Scientifique 1961, Institut Pasteur, 75015 Paris, France

CORRESPONDENCE Laurence Zitvogel: zitvogel{at}igr.fr

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)–ß, 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-ß^–/– 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.

F. Ghiringhelli and C. Ménard contributed equally to this work.

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