Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells

• Published in: Blood 2002-04, Vol.99 (7), p.2490-2498
• Main Authors: Deaglio, Silvia, Zubiaur, Mercedes, Gregorini, Armando, Bottarel, Flavia, Ausiello, Clara M., Dianzani, Umberto, Sancho, Jaime, Malavasi, Fabio
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Antigens, CD - immunology; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; Biological and medical sciences; Calcium - metabolism; Cytokines - biosynthesis; Cytokines - genetics; Cytotoxicity, Immunologic; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunity, Cellular; Immunobiology; Killer Cells, Natural - immunology; Leukemia, Lymphoid - immunology; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Membrane Glycoproteins; Multienzyme Complexes - immunology; NAD+ Nucleosidase - deficiency; NAD+ Nucleosidase - genetics; NAD+ Nucleosidase - immunology; Phosphotyrosine - metabolism; Receptors, IgG - immunology; Recombinant Proteins - immunology; Signal Transduction - immunology; Thymoma - immunology; Thymus Neoplasms - immunology; Transfection; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.7.2490

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-γ, 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.