International Immunology, Vol. 13, No. 4, 397-409,
April 2001
© 2001 Japanese Society for Immunology
Signaling through CD38 induces NK cell activation
1 Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino, Italy
2 Department of Cellular Biology and Immunology, Instituto de Parasitologia y Biomedicina, CSIC, 18071 Granada, Spain
3 National Institutes of Health (ISS), 00161 Roma, Italy
4 Department of Experimental Medicine, Section of Human Anatomy, University of Genova, 16100 Genova, Italy
Correspondence to: F. Malavasi, Laboratorio di Immunogenetica, Dipartimento di Genetica, Biologia e Biochimica, Via Santena 19, 10126 Torino, Italy
Human CD38 is a signal transduction molecule, and, concurrently, an ectoenzyme catalyzing the synthesis and degradation of cyclic ADP-ribose (cADPR), a potent Ca2+ mobilizer. One facet of CD38 that has not yet been addressed is its role in NK cells. To this end, the events triggered by CD38 ligation with agonistic mAb were analyzed on freshly purified human NK cells. Ligation was followed by (i) a significant rise in the intracellular level of Ca2+, (ii) increased expression of HLA class II and CD25, and (iii) tyrosine phosphorylation of discrete cytoplasmic substrates. The phosphorylation cascade involved CD3-
and Fc
RI
chains, -associated protein (ZAP)-70 and the proto-oncogene product c-Cbl. NK effector functions were then analyzed: CD38 signaling was able (iv) to induce release of IFN- and, more prominently, of granulocyte macrophage colony stimulating factor, as assessed by measuring both mRNA and protein products; and, lastly, (v) to induce cytolytic effector functions on target cells after IL-2 activation, as shown both by cytotoxicity assays and ultrastructural changes. The tyrosine-phosphorylated substrates and all the effects mediated by CD38 were similar to those observed following triggering via CD16 (FcRIIIA); moreover, Ca2+ mobilization via CD38 no longer operated in NK-derived cell lines lacking CD16. These results suggest that the activation signals transduced by CD38 in NK cells elicit relevant cellular events. The effects are similar to those elicited via CD16 and possibly rely on common signaling pathways.
Keywords: calcium, CD16, ectoenzymes, surface receptors, tyrosine phosphorylation
Transmitting editor: C. Terhorst
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