CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellularregulated kinase activation, leading to cytotoxic function of human NK cells

The CD94/NKG2-A complex is the inhibitory receptor for the nonclassical MHC class I molecule HLA-E on human NK cells. Here we studied the molecular me chanisms underlying the inhibitory activity of CD94/NKG2-A on NK cell funct ions by analyzing its interference on CD16-initiated signaling pathways inv olved in the control of cytolytic activity. Both tyrosine phosphorylation a nd activation of Syk kinase together with tyrosine phosphorylation of CD16 receptor zeta subunit are markedly inhibited by the coengagement of CD94/NK G2-A complex. As a downstream consequence, CD94/NKG2-A cross-linking impair s the CD16-induced; activation of extracellular regulated kinases (ERKs), a pathway involved in NK cytotoxic function. The block of ERK activation is exerted at an early, PTK-dependent stage in the events leading to p21(ras) activation, as the CD16-induced tyrosine phosphorylation of Shc adaptor pro tein and the formation of Shc/Grb-2 complex are abrogated by CD94/NKG2-A si multaneous engagement. Our observations indicate that CD94/NKG2-A inhibits the CD16-triggered activation of two signaling pathways involved in the cyt otoxic activity of NK cells. They thus provide molecular evidence to explai n the inhibitory function of CD94/NKG2-A receptor on NK effector functions.