title: Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily.
abstract: Herein, we show that CD8(dull), CD8(intermediate), and CD8(bright) natural killer (NK) cell clones can be identified. Triggering of CD8 with its natural ligand(s), represented by soluble HLA class I (sHLA-I), isolated either from serum of healthy donors or from HLA-I(-) 721.221 lymphoblastoid cell line transfected with HLA-A2, -Cw4, and -Bw46 alleles, or HLA-G1 leads to NK cell apoptosis. The magnitude of this effect directly correlated with the level of CD8 expression. sHLA-I-induced apoptosis depends on the interaction with CD8, as it was inhibited by masking this molecule with specific monoclonal antibodies (mAbs). Moreover, sHLA-I or CD8 cross-linking with specific mAbs elicited intracellular calcium increases, Fas ligand (FasL) messenger RNA transcription, and FasL secretion, which were needed for delivering the death signal. Indeed, this apoptosis was inhibited by preincubation of NK cell clones with Fas or FasL antagonist mAbs, indicating that the Fas/FasL pathway is involved. Furthermore, members of the inhibitory receptor superfamily, such as CD94/NKG2 complex or killer inhibitory receptors, were shown to exert an inhibitory effect on sHLA-I-mediated apoptosis and secretion of FasL. These findings suggest that interaction between sHLA-I and CD8 evokes an apoptotic signal that is down-regulated by inhibitory receptor superfamily that function as survival receptors in NK cells.
authors.affiliation: Laboratory of Immunology, National Cancer Research Institute, Genoa, Italy.
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Spaggiari
authors.forename: Paola
authors.initials: P
authors.lastname: Contini
authors.forename: Roberta
authors.initials: R
authors.lastname: Carosio
authors.forename: Marica
authors.initials: M
authors.lastname: Arvigo
authors.forename: Massimo
authors.initials: M
authors.lastname: Ghio
authors.forename: Daniela
authors.initials: D
authors.lastname: Oddone
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dondero
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Puppo
authors.forename: Francesco
authors.initials: F
authors.lastname: Indiveri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016827:CD8 Antigens / Q000032:analysis / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D015536:Down-Regulation; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011971:Receptors, Immunologic / Q000502:physiology; D054340:Receptors, KIR; D012995:Solubility
chemical_list: D016827:CD8 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D054340:Receptors, KIR