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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.

Original publication

DOI

10.1084/jem.20040780

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

11/10/2004

Volume

200

Pages

1063 - 1074

Addresses

Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 ONN, England, UK.

Keywords

Antigen-Presenting Cells, T-Lymphocytes, Animals, Mice, Glycoproteins, Adaptor Proteins, Signal Transducing, Complement Membrane Attack Complex, Lymphocyte Function-Associated Antigen-1, Integrins, Receptors, Antigen, T-Cell, Phosphoproteins, Interleukin-2, Lymphocyte Activation, Binding Sites, src Homology Domains, Complement System Proteins