The Journal of Experimental Medicine
Avanti Polar Lipids
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Published online 11 October 2004 doi:10.1084/jem.20040780
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 1063-1074
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ADAP–SLP-76 Binding Differentially Regulates Supramolecular Activation Cluster (SMAC) Formation Relative to T Cell–APC Conjugation

Hongyan Wang1, Fiona E. McCann2, John D. Gordan3, Xiang Wu1, Monika Raab3, Talat H. Malik1, Daniel M. Davis2, and Christopher E. Rudd1,3

1 Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
2 Department of Biological Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, England, UK
3 Department of Cell and Molecular Biology, Harvard University, Cambridge, MA 02115

Address correspondence to Christopher E. Rudd, Molecular Immunology Section, Dept. of Immunology, Imperial College London, Hammersmith Campus, Du Cane Rd., London W12 ONN, England, UK. Phone: 44-20-8383-8421; Fax: 44-20-8383-8434; email: c.rudd{at}ic.ac.uk

T cell–APC conjugation as mediated by leukocyte function-associated antigen-1 (LFA-1)–intercellular adhesion molecule (ICAM)-1 binding is followed by formation of the supramolecular activation cluster (SMAC) at the immunological synapse. The intracellular processes that regulate SMAC formation and its influence on T cell function are important questions to be addressed. Here, using a mutational approach, we demonstrate that binding of adaptor adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76 differentially regulates peripheral SMAC (pSMAC) formation relative to conjugation. Although mutation of the YDDV sites (termed M12) disrupted SLP-76 SH2 domain binding and prevented the ability of ADAP to increase conjugation and LFA-1 clustering, M12 acted selectively as a dominant negative (DN) inhibitor of pSMAC formation, an effect that was paralleled by a DN effect on interleukin-2 production. ADAP also colocalized with LFA-1 at the immunological synapse. Our findings identify ADAP–SLP-76 binding as a signaling event that differentially regulates SMAC formation, and support a role for SMAC formation in T cell cytokine production.

Key Words: integrins • adaptor proteins • immunological synapse

Abbreviations used in this paper: ADAP, adaptor adhesion and degranulation promoting adaptor protein; DN, dominant negative; HA, hemaglutinin; ICAM, intercellular adhesion molecule; LFA-1, leukocyte function-associated antigen-1; pSMAC, peripheral SMAC; SMAC, supramolecular activation cluster; Ttox, tetanus toxoid; WASP, Wiskot Aldrich Syndrome protein.


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