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...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2008.04.019