Positive and negative signaling through SLAM receptors regulate synapse organization and thresholds of cytolysis.
X-linked lymphoproliferative syndrome, characterized by fatal responses to Epstein-Barr virus infection, is caused by mutations affecting the adaptor SAP, which links SLAM family receptors to downstream signaling. Although cytotoxic defects in SAP-deficient T cells are documented, the mechanism remains unclear. We show that SAP-deficient murine CD8(+) T cells exhibited normal cytotoxicity against fibrosarcoma targets, yet had impaired adhesion to and killing of B cell and low-avidity T cell targets. SAP-deficient cytotoxic lymphocytes showed specific defects in immunological synapse organization with these targets, resulting in inefficient actin clearance. In the absence of SAP, signaling through the SLAM family members Ly108 and 2B4 resulted in increased recruitment of the SHP-1 phosphatase, associated with altered SHP-1 localization and decreased activation of Src kinases at the synapse. Hence, SAP and SLAM receptors regulate positive and negative signals required for organizing the T cell:B cell synapse and setting thresholds for cytotoxicity against distinct cellular targets.
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Fang
F
Zhao
Jennifer L
JL
Cannons
Mala
M
Dutta
Gillian M
GM
Griffiths
Pamela L
PL
Schwartzberg
D000199:Actins / Q000032:analysis; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D000950:Antigens, Ly / Q000276:immunology*; D001402:B-Lymphocytes; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018385:Centrosome / Q000648:ultrastructure; D003599:Cytoskeleton / Q000648:ultrastructure; D003602:Cytotoxicity, Immunologic; D005354:Fibrosarcoma / Q000473:pathology; D054992:Immunological Synapses / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000473:pathology; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011971:Receptors, Immunologic / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D015703:Antigens, CD; D000950:Antigens, Ly; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D010744:Phosphoric Monoester Hydrolases; D011971:Receptors, Immunologic; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D019061:src-Family Kinases; C490007:Cd244a protein, mouse; C499569:Sh2d1a protein, mouse; C000604063:Slamf6 protein, mouse