RasIndependentpathwayinNKcellmediatedcytotoxicity

NK (natural killer) cells are lymphocytes distinct from B and T cells that induce perforin-mediated lysis of tumor cells and virus-infected cells. NK cell-mediated cytotoxicity is activated by glycoproteins on the cell surface (activating receptors) and inhibited by MHC-1 with self-peptide bound. The MHC-1 inhibitory signal through Ig-family or lectin receptors prevents NK cells from killing normal cells. Abnormal MHC-1 expression in infected or tumor cells results in the release of perforin, the lysis of the abnormal cell and the release of cytokines that stimulate the immune response. MAP kinase inhibitors but not ras inhibitors are able to block NK cell cytotoxicity, indicating that the pathway can function by a ras-independent manner that involves the MAP kinase pathway. This pathway includes phosphoinositide-3-kinase (PI3K) as a key component, followed by Rac1 and the exchange factor Vav. The tyrosine kinase SYK and LAT may provide an additional pathway for activation of MAP kinases leading to NK cell activation, and also Pyk-2 activation by integrins. The protein tyrosine phosphatase SHP-1 appears to mediate the cytotoxicity inhibitory signal that blocks lysis of normal cells. The balance of these positive and negative signaling pathways regulates the role of NK cells in the immune response.

Contributor: Glenn Croston, PhD

REFERENCES: Brumbaugh KM et al., J Exp Med 1997 Dec 15;186(12):1965-74, Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. Galandrini R, Palmieri G, Piccoli M, Frati L, Santoni A., J Immunol 1999 Mar 15;162(6):3148-52, Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity. Gismondi A et al., J Immunol 2000 Mar 1;164(5):2272-6, Cutting edge: functional role for proline-rich tyrosine kinase 2 in NK cell-mediated natural cytotoxicity. Jiang K et al., Nat Immunol 2000 Nov;1(5):419-25, Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Wei S, Gilvary DL, Corliss BC, Sebti S, Sun J, Straus DB, Leibson PJ, Trapani JA, Hamilton AD, Weber MJ, Djeu JY., J Immunol 2000 Oct 1;165(7):3811-9, Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway.