DNAM-1 controls NK cell activation via an ITT-like motif

• Published in: The Journal of experimental medicine 2015-11, Vol.212 (12), p.2165-2182
• Main Authors: Zhang, Zhanguang, Wu, Ning, Lu, Yan, Davidson, Dominique, Colonna, Marco, Veillette, André
• Format: Article
• Language: English
• Subjects: Actins - immunology; Actins - metabolism; Amino Acid Motifs - genetics; Amino Acid Motifs - immunology; Animals; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; Calcium - immunology; Calcium - metabolism; Cell Line; Cell Line, Tumor; Cell Survival - genetics; Cell Survival - immunology; Cytokines - immunology; Cytokines - metabolism; Enzyme Activation - immunology; Extracellular Signal-Regulated MAP Kinases - immunology; Extracellular Signal-Regulated MAP Kinases - metabolism; GRB2 Adaptor Protein - genetics; GRB2 Adaptor Protein - immunology; GRB2 Adaptor Protein - metabolism; Humans; Immunoblotting; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Polymerization; Protein Binding - immunology; Proto-Oncogene Proteins c-akt - immunology; Proto-Oncogene Proteins c-akt - metabolism; RNA Interference; Signal Transduction - genetics; Signal Transduction - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20150792

DNAM-1 (CD226) is an activating receptor expressed on natural killer (NK) cells, CD8(+) T cells, and other immune cells. Upon recognition of its ligands, CD155 and CD112, DNAM-1 promotes NK cell-mediated elimination of transformed and virus-infected cells. It also has a key role in expansion and maintenance of virus-specific memory NK cells. Herein, the mechanism by which DNAM-1 controls NK cell-mediated cytotoxicity and cytokine production was elucidated. Cytotoxicity and cytokine production triggered by DNAM-1 were mediated via a conserved tyrosine- and asparagine-based motif in the cytoplasmic domain of DNAM-1. Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3' kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. We propose that DNAM-1 promotes NK cell activation via an immunoreceptor tyrosine tail (ITT)-like motif coupling DNAM-1 to Grb2 and other downstream effectors.