Costimulatory Molecule DNAM-1 Is Essential for Optimal Differentiation of Memory Natural Killer Cells during Mouse Cytomegalovirus Infection

• Published in: Immunity Vol. 40; no. 2; pp. 225 - 234
• Main Authors: Nabekura, Tsukasa, Kanaya, Minoru, Shibuya, Akira, Fu, Guo, Gascoigne, Nicholas R.J., Lanier, Lewis L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.02.2014; Elsevier (Cell Press); Elsevier Limited
• Subjects: Animals; Antigens; Antigens, Differentiation, T-Lymphocyte - metabolism; Cell Differentiation; Cytomegalovirus; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - physiopathology; Cytotoxicity; Disease Models, Animal; Immune system; Immunity, Innate - genetics; Infections; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Ligands; Lymphocytes; Mice; Mice, Inbred C57BL; Murine cytomegalovirus; Muromegalovirus - immunology; Spleen; Statistical methods
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2013.12.011

Recent studies demonstrate that natural killer (NK) cells have adaptive immune features. Here, we investigated the role of the costimulatory molecule DNAM-1 in the differentiation of NK cells in a mouse model of cytomegalovirus (MCMV) infection. Antibody blockade of DNAM-1 suppressed the expansion of MCMV-specific Ly49H+ cells during viral infection and inhibited the generation of memory NK cells. Similarly, DNAM-1-deficient (Cd226−/−) Ly49H+ NK cells exhibited intrinsic defects in expansion and differentiation into memory cells. Src-family tyrosine kinase Fyn and serine-threonine protein kinase C isoform eta (PKCη) signaling through DNAM-1 played distinct roles in the generation of MCMV-specific effector and memory NK cells. Thus, cooperative signaling through DNAM-1 and Ly49H are required for NK cell-mediated host defense against MCMV infection. •DNAM-1 is required for the expansion and generation of memory NK cells•Fyn and PKCη play distinct role in DNAM-1 signaling in Ly49H+ NK cells•DNAM-1 is dynamically regulated on NK cells during MCMV infection•MCMV infection upregulates DNAM-1 ligands on dendritic cells and macrophages