Signaling through CD38 induces NK cell activation

Human CD38 is a signal transduction molecule, and, concurrently, an ectoenz yme 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. Ligat ion was followed by (i) a significant rise in the intracellular level of Ca 2+, (ii) increased expression of HLA class II and CD25, and (iii) tyrosine phosphorylation of discrete cytoplasmic substrates, The phosphorylation cas cade involved CDS-S and Fc epsilon Rl gamma chains, zeta -associated protei n (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-gamma 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 activati on, as shown both by cytotoxicity assays and ultrastructural changes. The t yrosine-phosphorylated substrates and all the effects mediated by CD38 were similar to those observed following triggering via CD16 (Fc gamma RIIIA); moreover, Ca2+ mobilization via CD38 no longer operated in NK-derived cell lines lacking CD16. These results suggest that the activation signals trans duced by CD38 in NK cells elicit relevant cellular events. The effects are similar to those elicited via CD16 and possibly rely on common signaling pa thways.