Model of the NKG2D signaling pathway in CTLs. The NKG2D cytolytic signaling pathway involves PLC-γ2, Vav1, and PI3-K activation (60). How these upstream signaling events are interconnected in CTLs remains to be determined. NKG2D-mediated cytolysis requires activation of cPLA₂ and AA release, suggesting that the level of calcium mobilization achieved upon NKG2D cross-linking is insufficient to allow membrane fusion events and exocytosis. Cytosolic PLA₂ activation itself is mediated through two independent pathways, Vav-1→JNKK1/2→JNK1/2→cPLA₂ and PI3-K→MEK1/2→ERK→cPLA₂. It is likely that these pathways also promote granule polarization (62, 63, 67). In addition, cPLA₂ activation is also required for NKG2D cytolytic co-stimulatory functions. Interestingly, IL-15, which licenses NKG2D killing in CTLs (6), enhances NKG2D-mediated JNK, ERK and cPLA₂ phosphorylation, and AA release. Once released, AA can potentially be reincorporated into phospholipids, mediate the biosynthesis of eicosanoids and induce granulocyte activation.