Natural Killer Cell Group 7 Sequence in Cytotoxic Cells Optimizes Exocytosis of Lytic Granules Essential for the Perforin-Dependent, but Not Fas Ligand-Dependent, Cytolytic Pathway.

Cytotoxic cells, such as CD8 T cells or NK cells, have been shown to eliminate virus-infected cells or transformed cells primarily via two pathways: the perforin/granzyme-dependent pathway and the Fas ligand-Fas pathway; however, the precise cytolytic mechanisms have not been clarified thoroughly. In our previous study, we demonstrated that a T-box transcription factor, Eomesodermin (Eomes), may play important roles in activating the perforin pathway besides inducing perforin and granzyme B mRNA expression. In this study, we identified natural killer cell group 7 sequence (Nkg7), a molecule induced by Eomes, to be found critical for perforin-dependent cytolysis. Nkg7 mRNA expression in leukocytes from normal mice was mainly restricted to cells with cytotoxicity such as NK cells, NKT cells, and activated CD8 T cells. The cytolytic activity of NK cells or CD8 CTLs from Nkg7-deficient mice against Fas-negative target cells was reduced significantly, whereas Fas ligand-mediated cytolysis by Nkg7-deficient CTLs was not impaired. Further, translocation of granule membrane protein CD107a to the cell surface upon CD3 stimulation was defective in CD8 CTLs from Nkg7 knockout, whereas surface induction of another granule membrane protein, CD63, was almost normal. In addition, analyses of lytic granules in CTLs by electron microscopy revealed that the number of lytic granules with dense cores was significantly reduced in Nkg7-knockout CTLs. These results indicate that Nkg7 may specifically contribute to efficient cytolysis via the perforin/granzyme pathway by enhancing the exocytosis of a particular type of lytic granules.