title: CD59 is physically and functionally associated with natural cytotoxicity receptors and activates human NK cell-mediated cytotoxicity.
abstract: Triggering of cytotoxicity in human NK cells is induced by the combined engagement of several triggering receptors. These include primary receptors such as NKG2D and the natural cytotoxicity receptors (NCR) NKp30, NKp46 and NKp44, while other molecules, including 2B4, NTB-A and NKp80, function as co-receptors. As reported in the present study, during an attempt to identify novel NK receptors or co-receptors, we found that CD59 functions as a co-receptor in human NK cell activation; engagement of CD59 by specific mAb delivers triggering signals to human NK cells, resulting in enhancement of cytotoxicity. Similar to other NK co-receptors, the triggering function of CD59, a glycosylphosphatidylinositol (GPI)-linked protein, depends on the simultaneous engagement of primary receptors such as NCR. Accordingly, CD59-dependent triggering was virtually restricted to NK cells expressing high surface densities of NKp46, and mAb-mediated modulation of NKp46 resulted in markedly decreased responses to anti-CD59 mAb. Biochemical analysis revealed that CD59 is physically associated with NKp46 and NKp30. Moreover, engagement of CD59 resulted in tyrosine phosphorylation of CD3zeta chains associated with these NCR, but not those associated with CD16. Thus, CD59-mediated costimulation of NK cells requires direct physical interaction of this GPI-linked protein with primary triggering NK receptors.
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marcenaro
authors.forename: Raffaella
authors.initials: R
authors.lastname: Augugliaro
authors.forename: Michela
authors.initials: M
authors.lastname: Falco
authors.forename: Roberta
authors.initials: R
authors.lastname: Castriconi
authors.forename: Silvia
authors.initials: S
authors.lastname: Parolini
authors.forename: Simona
authors.initials: S
authors.lastname: Sivori
authors.forename: Elisa
authors.initials: E
authors.lastname: Romeo
authors.forename: Romano
authors.initials: R
authors.lastname: Millo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018957:CD59 Antigens / Q000502:physiology*; D019556:COS Cells; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D017452:Receptors, IgG / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D018957:CD59 Antigens; C112260:NCR1 protein, human; C112837:NCR2 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D017452:Receptors, IgG; D011971:Receptors, Immunologic