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

J Exp Med. 2015 Nov 16;212(12):2165-82. doi: 10.1084/jem.20150792. Epub 2015 Nov 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • T Lineage-Specific Activation Antigen 1

Substances

  • Actins
  • Antigens, Differentiation, T-Lymphocyte
  • T Lineage-Specific Activation Antigen 1
  • Cytokines
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Calcium