Cross-linking of CD45 on NK cells stimulates p56lck-mediated tyrosine phosphorylation and IFN-gamma production.

The cross-linking of low-affinity Fc gamma RIIIA on NK cells with specific mAbs or aggregated IgG stimulates both cytotoxic activity and cytokine production. In addition, the interaction of NK cells with certain tumor cells can also stimulate cytokine production and cytotoxic activity. The identity of the molecules on the tumor cell or NK cells involved in this stimulation currently has not been defined. We have reported previously that cross-linking of CD45 and the CD45RO isoform on IL-2-activated NK cells or the NK cell line NK3.3 results in the stimulation of IFN-gamma production. We report here that this effect is specific, because cross-linking of CD45 does not stimulate the expression of cytotoxic activity. Consistent with studies suggesting that cross-linking of CD45 results in reduced phosphatase activity, inhibition of tyrosine phosphatase activity by pharmacologic means also resulted in enhanced tyrosine kinase activity and, ultimately, increased IFN-gamma production. Biochemical analyses and immunofluorescence studies suggest that the tyrosine kinase associated with CD45 is p56lck and that cross-linking of CD45 results in the activation of p56lck. Thus, CD45 may regulate p56lck kinase, which initiates the cascade of intracellular tyrosine phosphorylation events that lead to IFN-gamma transcription and secretion in NK 3.3 cells.