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T Cell Costimulation via the Integrin VLA-4 Inhibits the Actin-Dependent Centralization of Signaling Microclusters Containing the Adaptor SLP-76

Antigen-dependent T cell activation drives the formation of signaling microclusters containing the adaptor SLP-76. Costimulatory integrins regulate SLP-76 phosphorylation and could influence SLP-76 microclusters in the integrin-rich periphery of the immune synapse. We report that costimulation by th...

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Published in:	Immunity (Cambridge, Mass.) Mass.), 2008-06, Vol.28 (6), p.810-821
Main Authors:	Nguyen, Ken, Sylvain, Nicholas R., Bunnell, Stephen C.
Format:	Article
Language:	English
Subjects:	Actins - immunology Actins - metabolism Adaptor Proteins, Signal Transducing - metabolism Binding sites Cell adhesion & migration Cell culture Glass substrates Humans Hypotheses Integrin alpha4beta1 - immunology Integrin alpha4beta1 - metabolism Jurkat Cells Kinases Ligands Lymphocyte Activation Lymphocytes Mutation Phosphoproteins - metabolism Signal Transduction T cell receptors T-Lymphocytes - immunology ZAP-70 Protein-Tyrosine Kinase - metabolism
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description	Antigen-dependent T cell activation drives the formation of signaling microclusters containing the adaptor SLP-76. Costimulatory integrins regulate SLP-76 phosphorylation and could influence SLP-76 microclusters in the integrin-rich periphery of the immune synapse. We report that costimulation by the integrin VLA-4 (α4β1) required SLP-76 domains implicated in microcluster assembly. Pro-adhesive ligands enlarged the contact and increased the number of SLP-76 microclusters regardless of their costimulatory potential. Costimulatory VLA-4 ligands also prevented the centralization of SLP-76, promoted microcluster persistence, prolonged lateral interactions between SLP-76 and its upstream kinase, ZAP-70, and retained SLP-76 in tyrosine-phosphorylated peripheral structures. SLP-76 centralization was driven by dynamic actin polymerization and was correlated with inward actin flows. VLA-4 ligation retarded these flows, even in the absence of SLP-76. These data suggest a widely applicable model of costimulation, in which integrins promote sustained signaling by attenuating cytoskeletal movements that drive the centralization and inactivation of SLP-76 microclusters.
doi_str_mv	10.1016/j.immuni.2008.04.019
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subjects	Actins - immunology Actins - metabolism Adaptor Proteins, Signal Transducing - metabolism Binding sites Cell adhesion & migration Cell culture Glass substrates Humans Hypotheses Integrin alpha4beta1 - immunology Integrin alpha4beta1 - metabolism Jurkat Cells Kinases Ligands Lymphocyte Activation Lymphocytes Mutation Phosphoproteins - metabolism Signal Transduction T cell receptors T-Lymphocytes - immunology ZAP-70 Protein-Tyrosine Kinase - metabolism
title	T Cell Costimulation via the Integrin VLA-4 Inhibits the Actin-Dependent Centralization of Signaling Microclusters Containing the Adaptor SLP-76
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