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Critical and Differential Roles of NKp46- and NKp30-Activating Receptors Expressed by Uterine NK Cells in Early Pregnancy¹

Hicham El Costa^*,, Audrey Casemayou^*,, Maryse Aguerre-Girr^*,, Magali Rabot^*,, Alain Berrebi^*,, Olivier Parant^*,, Muriel Clouet-Delannoy, Letizia Lombardelli, Nabila Jabrane-Ferrat^*,, Daniel Rukavina^¶, Armand Bensussan^||, Marie-Pierre Piccinni, Philippe Le Bouteiller^2,*,, and Julie Tabiasco^*,

^* Institut National de la Santé et de la Recherche Médicale; U563; Toulouse, France; Université Toulouse III, France; Centre Hospitalier Universitaire Toulouse, Hôpital Paule de Viguier, Toulouse, France; Centre of Excellence for Research, Transfer and High Education DENOTHE, University of Florence and Department of Internal Medicine-Immunoallergology Unit, Florence, Italy; ^¶ Medical Faculty, Department of Physiology and Immunology, Rijeka, Croatia; and ^|| Institut National de la Santé et de la Recherche Médicale, U841, Faculté de Médecine de Créteil, Créteil, France

In early human pregnancy, uterine decidual NK cells (dNK) are abundant and considered as cytokine producers but poorly cytotoxic despite their cytolytic granule content, suggesting a negative control of this latter effector function. To investigate the basis of this control, we examined the relative contribution to the cytotoxic function of different activating receptors expressed by dNK. Using a multicolor flow cytometry analysis, we found that freshly isolated dNK exhibit a unique repertoire of activating and inhibitory receptors, identical among all the donors tested. We then demonstrated that in fresh dNK, mAb-specific engagement of NKp46-, and to a lesser extent NKG2C-, but not NKp30-activating receptors induced intracellular calcium mobilization, perforin polarization, granule exocytosis and efficient target cell lysis. NKp46-mediated cytotoxicity is coactivated by CD2 but dramatically blocked by NKG2A coengagement, indicating that the dNK cytotoxic potential could be tightly controlled in vivo. We finally found that in dNK, mAb-specific engagement of NKp30, but not NKp46, triggered the production of IFN-, TNF-, MIP-1, MIP-1β, and GM-CSF proinflammatory molecules. These data demonstrate a differential, controlled role of NKp46- and NKp30-activating receptors expressed by dNK that could be critical for the outcome of pregnancy and the killing of uterine cells infected by pathogens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Institut National de la Santé et de la Recherche Médicale (to P.L.B. and A.B.), Université Paul Sabatier de Toulouse, Centre Hospitalier Universitaire Toulouse (to P.L.B.) and the European NoE Embryo Implantation Control Network (EMBIC) (LSHM-CT-2004-512040) (to P.L.B., D.R., and M.-P.P.). H.E.C. was supported by Centre National de la Recherche Scientifique Libanais and EMBIC. J.T. was supported by EMBIC.

² Address correspondence and reprint requests to Dr. Philippe Le Bouteiller, Institut National de la Santé et de la Recherche Médicale, U563, Centre de Physiopathologie de Toulouse-Purpan, Bat. A, BP 3028, 31024 Toulouse cedex 3, France. E-mail address: philippe.le-bouteiller{at}inserm.fr

³ Abbreviations used in this paper: dNK, decidual NK cell; PB, peripheral blood.