title: Ligation of CD8alpha on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity.
abstract: It has been previously shown that the subset of human natural killer (NK) cells which express CD8 in a homodimeric alpha/alpha form are more cytotoxic than their CD8- counterparts but the mechanisms behind this differential cytolytic activity remained unknown. Target cell lysis by CD8- NK cells is associated with high levels of effector cell apoptosis, which is in contrast to the significantly lower levels found in the CD8alpha+ cells after lysis of the same targets. We report that cross-linking of the CD8alpha chains on NK cells induces rapid rises in intracellular Ca2+ and increased expression of CD69 at the cell surface by initiating the influx of extracellular Ca2+ ions. We demonstrate that secretion of cytolytic enzymes initiates NK-cell apoptosis from which CD8alpha+ NK cells are protected by an influx of exogenous calcium following ligation of CD8 on the NK-cell surface. This ligation is through interaction with fellow NK cells in the cell conjugate and can occur when the target cells lack major histocompatibility complex (MHC) Class I expression. Protection from apoptosis is blocked by preincubation of the NK cells with anti-MHC Class I antibody. Thus, in contrast to the CD8- subset, CD8alpha+ NK cells are capable of sequential lysis of multiple target cells.
authors.affiliation: Department of Haematology, Royal Free & University College Medical School, London, United Kingdom. e.addsion@medsch.ucl.ac.uk
authors.forename: Elena G
authors.initials: EG
authors.lastname: Addison
authors.forename: Janet
authors.initials: J
authors.lastname: North
authors.forename: Ismail
authors.initials: I
authors.lastname: Bakhsh
authors.forename: Chloe
authors.initials: C
authors.lastname: Marden
authors.forename: Sumaira
authors.initials: S
authors.lastname: Haq
authors.forename: Samia
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Reza
authors.initials: R
authors.lastname: Malayeri
authors.forename: R Gitendra
authors.initials: RG
authors.lastname: Wickremasinghe
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Davies
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lowdell
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D016827:CD8 Antigens / Q000097:blood / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000097:blood; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D053804:Granzymes; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000097:blood; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000097:blood / Q000276:immunology; D054340:Receptors, KIR; D012697:Serine Endopeptidases / Q000097:blood; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D015815:Cell Adhesion Molecules; D006680:HLA Antigens; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054353:Perforin; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human