SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility.
Although adaptor ADAP (FYB) and its binding to SLP-76 has been implicated in TcR-induced "inside-out" signaling for LFA-1 activation in T cells, little is known regarding its role in LFA-1-mediated "outside-in" signaling. In this study, we demonstrate that ADAP and SLP-76-ADAP binding are coupled to LFA-1 costimulation of IL-2 production, F-actin clustering, cell polarization, and T cell motility. LFA-1 enhancement of anti-CD3-induced IL-2 production was completely dependent on SLP-76-ADAP binding. Further, anti-CD3 was found to require CD11a ligation by antibody or ICAM1 to cause T cell polarization. ADAP augmented this polarization induced by anti-CD3/CD11a, but not by anti-CD3 alone. ADAP expression with LFA-1 ligation alone was sufficient to polarize T cells directly and to increase T cell motility whereas the loss of ADAP in ADAP-/- primary T cells reduced motility. A mutant lacking SLP-76-binding sites (M12) blocked LFA-1 costimulation of IL-2 production, polarization, and motility. LFA-1-ADAP polarization was also dependent on src kinases, Rho GTPases, phospholipase C, and phosphoinositol 3-kinase. Our findings provide evidence of an obligatory role for the SLP-76-ADAP module in LFA-1-mediated costimulation in T cells.
Wang
Hongyan
H
Cell Signaling Section, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
Wei
Bin
B
Bismuth
Georges
G
Rudd
Christopher E
CE
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001665:Binding Sites; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D017252:CD3 Complex; D002867:Chromones; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D018799:Intercellular Adhesion Molecule-1; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011743:Pyrimidines; D020741:rho GTP-Binding Proteins; D019061:src-Family Kinases; C412373:AG 1879; C491468:Fyb protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one