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.
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18 October 2004
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October 11 2004
ADAP–SLP-76 Binding Differentially Regulates Supramolecular Activation Cluster (SMAC) Formation Relative to T Cell–APC Conjugation
Hongyan Wang,
Hongyan Wang
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
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Fiona E. McCann,
Fiona E. McCann
2Department of Biological Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, England, UK
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John D. Gordan,
John D. Gordan
3Department of Cell and Molecular Biology, Harvard University, Cambridge, MA 02115
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Xiang Wu,
Xiang Wu
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
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Monika Raab,
Monika Raab
3Department of Cell and Molecular Biology, Harvard University, Cambridge, MA 02115
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Talat H. Malik,
Talat H. Malik
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
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Daniel M. Davis,
Daniel M. Davis
2Department of Biological Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, England, UK
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Christopher E. Rudd
Christopher E. Rudd
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
3Department of Cell and Molecular Biology, Harvard University, Cambridge, MA 02115
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Hongyan Wang
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
Fiona E. McCann
2Department of Biological Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, England, UK
John D. Gordan
3Department of Cell and Molecular Biology, Harvard University, Cambridge, MA 02115
Xiang Wu
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
Monika Raab
3Department of Cell and Molecular Biology, Harvard University, Cambridge, MA 02115
Talat H. Malik
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
Daniel M. Davis
2Department of Biological Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, England, UK
Christopher E. Rudd
1Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK
3Department 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: [email protected]
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.
Received:
April 20 2004
Accepted:
August 09 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2004
J Exp Med (2004) 200 (8): 1063–1074.
Article history
Received:
April 20 2004
Accepted:
August 09 2004
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Citation
Hongyan Wang, Fiona E. McCann, John D. Gordan, Xiang Wu, Monika Raab, Talat H. Malik, Daniel M. Davis, Christopher E. Rudd; ADAP–SLP-76 Binding Differentially Regulates Supramolecular Activation Cluster (SMAC) Formation Relative to T Cell–APC Conjugation . J Exp Med 18 October 2004; 200 (8): 1063–1074. doi: https://doi.org/10.1084/jem.20040780
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