Signaling lymphocytic activation molecule (SLAM) regulates T cellular cytotoxicity.
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.
Henning
G
G
Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, Erlangen, Germany.
Kraft
M S
MS
Derfuss
T
T
Pirzer
R
R
de Saint-Basile
G
G
Aversa
G
G
Fleckenstein
B
B
Meinl
E
E
D015703:Antigens, CD; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006567:Herpesvirus 2, Saimiriine / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011956:Receptors, Cell Surface; D022142:Secretory Vesicles / Q000378:metabolism; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; D002352:Carrier Proteins; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D019014:fas Receptor; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases