NK cell-mediated lysis of autologous antigen-presenting cells is triggeredby the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46

Interleukin-2 (IL-2)-activated polyclonal or clonal NK cells lysed autologo us antigen presenting cells (APC) through the engagement of the natural cyt otoxicity receptors (NCR) NKp30 and NKp46. NK cell-mediated cytolysis of AP C correlated with the surface density of these NCR. Indeed, NK cell clones bearing low amounts of NKp30 and NKp46 did not lyse autologous APC, whereas NK cell clones with bright expression of these NCR efficiently killed auto logous APC. Upon masking of NKp30 or NKp46 by specific monoclonal antibodie s a strong reduction (by 50%) of APC lysis could be detected and the comple te inhibition was achieved by the simultaneous masking of these NCR. Intere stingly, NK cell-mediated APC lysis was impaired by the phosphatidylinosito l 3-kinase (PI-3 K) inhibitors LY294002 or wortmannin. Similarly, these dru gs strongly reduced NK cell activation triggered by NKp30 or NKp46 in a re- directed killing assay as well as the activation of AM/PKB, substrate of PI -3 K, induced by the engagement of these receptors. Altogether, these findi ngs strongly suggest that NCR are responsible for the killing of autologous APC through the activation of PI-3 K.