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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2490-2498
IMMUNOBIOLOGY
Human CD38 and CD16 are functionally dependent and physically
associated in natural killer cells
Silvia Deaglio,
Mercedes Zubiaur,
Armando Gregorini,
Flavia Bottarel,
Clara M. Ausiello,
Umberto Dianzani,
Jaime Sancho, and
Fabio Malavasi
From the Laboratory of Immunogenetics, Department
of Genetics, Biology and Biochemistry, University of Torino
Medical School, Torino, Italy; the Experimental Medicine Research
Center, Torino, Italy; the Department of Cell Biology and Immunology,
Institute of Parasitology and Biomedicine, Consejo Superior de
Investigaciones Científicas, Granada, Spain; the Institute of
Biology and Genetics, University of Ancona Medical School, Ancona,
Italy; the Department of Medical Science, A. Avogadro University of
Eastern Piedmont, Novara, Italy; and the Department of Bacteriology and
Medical Mycology, Istituto Superiore di Sanità, Rome, 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- , 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.
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