T cell costimulation via the integrin VLA-4 inhibits the actin-dependent centralization of signaling microclusters containing the adaptor SLP-76

Immunity. 2008 Jun;28(6):810-21. doi: 10.1016/j.immuni.2008.04.019.


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 (alpha4beta1) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / immunology
  • Actins / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Humans
  • Integrin alpha4beta1 / immunology
  • Integrin alpha4beta1 / metabolism*
  • Jurkat Cells
  • Lymphocyte Activation*
  • Phosphoproteins / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*


  • Actins
  • Adaptor Proteins, Signal Transducing
  • Integrin alpha4beta1
  • Phosphoproteins
  • SLP-76 signal Transducing adaptor proteins
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human