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Identification of PVR (CD155) and Nectin-2 (CD112) as Cell Surface Ligands for the Human DNAM-1 (CD226) Activating Molecule

Cristina Bottino¹, Roberta Castriconi², Daniela Pende³, Paola Rivera², Marina Nanni^1,2, Barbara Carnemolla³, Claudia Cantoni^1,2,4, Jessica Grassi², Stefania Marcenaro¹, Nicolas Reymond⁵, Massimo Vitale³, Lorenzo Moretta^1,2,4, Marc Lopez⁵ and Alessandro Moretta^2,4

¹ Istituto Giannina Gaslini, 16148 Genova, Italy
² Dipartimento di Medicina Sperimentale, Università di Genova, 16132 Genova, Italy
³ Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy
⁴ Centro di Eccellenza per la Ricerca Biomedica, 16132 Genova, Italy
⁵ Institut de Biologie du Cancer et d'Immunologie, INSERM U.119, 13009 Marseille, France

Address correspondence to Alessandro Moretta M.D., Dipartimento di Medicina Sperimentale, Sezione di Istologia, Via G.B. Marsano 10, 16132 Genova, Italy. Phone: 39-010-35-37-868; Fax: 39-010-51-27-47; email: alemoret{at}unige.it

Human natural killer (NK) cells express a series of activating receptors and coreceptors that are involved in recognition and killing of target cells. In this study, in an attempt to identify the cellular ligands for such triggering surface molecules, mice were immunized with NK-susceptible target cells. On the basis of a functional screening, four mAbs were selected that induced a partial down-regulation of the NK-mediated cytotoxicity against the immunizing target cells. As revealed by biochemical analysis, three of such mAbs recognized molecules of 70 kD. The other mAb reacted with two distinct molecules of 65 and 60 kD, respectively. Protein purification followed by tryptic digestion and mass spectra analysis, allowed the identification of the 70 kD and the 65/60 kD molecules as PVR (CD155) and Nectin-2 / (CD112), respectively. PVR-Fc and Nectin-2-Fc soluble hybrid molecules brightly stained COS-7 cells transfected with the DNAM-1 (CD226) construct, thus providing direct evidence that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. Finally, the surface expression of PVR or Nectin-2 in cell transfectants resulted in DNAM-1–dependent enhancement of NK-mediated lysis of these target cells. This lysis was inhibited or even virtually abrogated upon mAb-mediated masking of DNAM-1 (on NK cells) or PVR or Nectin-2 ligands (on cell transfectants).

Key Words: natural killer cells • tumors • activating receptors • cellular ligands • protein sequencing

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