Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase Itk

NK cells are effector lymphocytes that can recognize and eliminate virally infected and transformed cells. NK cells express distinct activating receptors, including an ITAM-containing FcR complex that recognizes Ab-coated targets, and the DNAX-activating protein of 10 kDa-containing NKG2D receptor complex that recognizes stress-induced ligands. The regulatory role of specific tyrosine kinases in these pathways is incompletely understood. In this study, we show that., in activated human NK cells, the tyrosine kinase IL-2-inducible T cell kinase (Irk), differentially regulates distinct NK-activating receptors. Enhanced expression of Irk leads to increases in calcium mobilization, granule release, and cytotoxicity upon stimulation of the ITAM-containing FcR, suggesting that Irk positively regulates FcR-initiated cytotoxicity. In contrast, enhanced Irk expression decreases cytotoxicity and granule release downstream of the DNAX-activating protein of 10 kDa-containing NKG2D receptor, suggesting that Irk is involved in a pathway of negative regulation of NKG2D-initiated granule-mediated killing. Using a kinase mutant, we show that the catalytic activity of Irk is required for both the positive and negative regulation of these pathways. Complementary experiments where Irk expression was suppressed also showed differential regulation of the two pathways. These findings suggest that Irk plays a complex role in regulating the functions initiated by distinct NK cell-activating receptors. Moreover, understanding how these pathways may be differentially regulated has relevance in the setting of autoimmune diseases and antitumor immune responses where NK cells play key regulatory roles. The Journal of Immunology, 2007, 178: 3575-3582.