TY - JOUR
T1 - Positive and Negative Signaling through SLAM Receptors Regulate Synapse Organization and Thresholds of Cytolysis
AU - Zhao, Fang
AU - Cannons, Jennifer L.
AU - Dutta, Mala
AU - Griffiths, Gillian M.
AU - Schwartzberg, Pamela L.
N1 - Funding Information:
The authors would like to thank J. Reilley, R. Handon, S. Wincovitch, S. Anderson, and J. Fekecs for assistance. This work was funded in part by the intramural program of the National Human Genome Research Institute and by the Wellcome Trust (085880 to G.M.G.). F.Z. was a Scholar in the NIH-Oxford-Cambridge Scholars in Biomedical Research program.
PY - 2012/6/29
Y1 - 2012/6/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863001429&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.05.017
DO - 10.1016/j.immuni.2012.05.017
M3 - Article
C2 - 22683123
AN - SCOPUS:84863001429
SN - 1074-7613
VL - 36
SP - 1003
EP - 1016
JO - Immunity
JF - Immunity
IS - 6
ER -