Abstract
Signaling lymphocytic activation molecule (SLAM) is a CD2-related surface receptor expressed by activated T cells and B cells. SLAM is a self ligand and enhances T cellular proliferation and IFN-gamma production. A defective SLAM associated protein (SAP) causes X-linked lymphoproliferative syndrome (XLP), a frequently lethal mononucleosis based on the inability to control EBV. We report that SLAM augments TCR-mediated cytotoxicity. In normal CD4(+) and CD8(+) T cells, SLAM enhanced TCR-mediated cytotoxicity. In CD4(+) and CD8(+) Herpesvirus saimiri (H.saimiri) infected T cells, SLAM engagement alone triggered cytotoxicity. Using H.saimiri-transformed T cells as a model system we found that SLAM-engagement promotes the release of lytic granules and a CD95-independent killing that requires extracellular Ca(2+), cytoskeletal rearrangements, and signaling mediated by mitogen-activated protein kinase kinases MEK1/2. SLAM-enhanced cytotoxicity implies an immunoregulatory function by facilitating the elimination of APC and a role in overcoming infections with pathogens requiring a cytotoxic immune response.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD
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Calcium Signaling
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Cell Line, Transformed
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Cell Transformation, Viral
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Cells, Cultured
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Cytotoxicity Tests, Immunologic
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Cytotoxicity, Immunologic*
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Glycoproteins / genetics
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Glycoproteins / physiology*
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Herpesvirus 2, Saimiriine / physiology
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Humans
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Immunoglobulins / genetics
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Immunoglobulins / physiology*
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Intracellular Signaling Peptides and Proteins*
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Lymphocyte Activation
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Mitogen-Activated Protein Kinase Kinases / physiology
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Protein Serine-Threonine Kinases / physiology
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Protein-Tyrosine Kinases / physiology
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RNA, Messenger / biosynthesis
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Cell Surface
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Secretory Vesicles / metabolism
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family Member 1
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / virology
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fas Receptor / physiology
Substances
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Antigens, CD
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Carrier Proteins
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Glycoproteins
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Immunoglobulins
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Receptors, Cell Surface
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SH2D1A protein, human
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Signaling Lymphocytic Activation Molecule Associated Protein
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fas Receptor
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Signaling Lymphocytic Activation Molecule Family Member 1
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MAP2K2 protein, human
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases