title: Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells.
abstract: CD38, a surface glycoprotein of unrestricted lineage, is an ectoenzyme (adenosine diphosphate [ADP] ribosyl cyclase/cyclic ADP-ribose hydrolase) that regulates cytoplasmic calcium. The molecule also performs as a receptor, modulating cell-cell interactions and delivering transmembrane signals, despite showing a structural ineptitude to the scope. CD38 ligation by agonistic monoclonal antibodies induced signals leading to activation of the lytic machinery of natural killer (NK) cells from adults; similar signals could not be reproduced in YT and NKL, 2 CD16(-) human NK-like lines. It was hypothesized that CD38 establishes a functional cooperation with professional signaling molecules of the NK cell surface. The present work answers the question about the molecule exploited by CD38 for signaling in NK cells, using as a model CD16(-) NK lines genetically corrected for CD16 expression. Our results indicate that a functional CD16 molecule is a necessary and sufficient requisite for CD38 to control an activation pathway, which includes calcium fluxes, tyrosine phosphorylation of ZAP70 and mitogen-activated protein kinase, secretion of interferon-gamma, and cytotoxic responses. Fluorescence resonance energy transfer and cocapping experiments also showed a surface proximity between CD38 and CD16. These results were confirmed by using the NKL cell line, in which CD16(+) and CD16(-) variants were obtained without genetic manipulation. Together, our findings show CD38 to be a unique receptor molecule that cannot signal by itself but whose receptor function is rescued by functional and physical associations with a professional signaling structure that varies according to lineage and environment. This molecule is CD16 in NK cells.
authors.affiliation: Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Via Santena 19, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.forename: Mercedes
authors.initials: M
authors.lastname: Zubiaur
authors.forename: Armando
authors.initials: A
authors.lastname: Gregorini
authors.forename: Flavia
authors.initials: F
authors.lastname: Bottarel
authors.forename: Clara M
authors.initials: CM
authors.lastname: Ausiello
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.forename: Jaime
authors.initials: J
authors.lastname: Sancho
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology*; D007945:Leukemia, Lymphoid / Q000276:immunology; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes / Q000276:immunology; D009244:NAD+ Nucleosidase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019000:Phosphotyrosine / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013945:Thymoma / Q000276:immunology; D013953:Thymus Neoplasms / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D016207:Cytokines; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D017452:Receptors, IgG; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium