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

Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Via Santena 19, Turin, Italy.
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.
Mesh Terms:
ADP-ribosyl Cyclase, Antigens, CD, Antigens, CD38, Antigens, Differentiation, Calcium, Cytokines, Cytotoxicity, Immunologic, Humans, Immunity, Cellular, Killer Cells, Natural, Leukemia, Lymphoid, Membrane Glycoproteins, Multienzyme Complexes, NAD+ Nucleosidase, Phosphotyrosine, Receptors, IgG, Recombinant Proteins, Signal Transduction, Thymoma, Thymus Neoplasms, Transfection, Tumor Cells, Cultured
Blood Apr. 01, 2002; 99(7);2490-8 [PUBMED:11895784]
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