Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP

Curr Biol. 2003 Sep 16;13(18):1619-24. doi: 10.1016/j.cub.2003.08.005.


Actin polymerization at the immune synapse is required for T cell activation and effector function; however, the relevant regulatory pathways remain poorly understood. We showed previously that binding to antigen presenting cells (APCs) induces localized activation of Cdc42 and Wiskott-Aldrich Syndrome protein (WASP) at the immune synapse. Several lines of evidence suggest that Tec kinases could interact with WASP-dependent actin regulatory processes. Since T cells from Rlk-/-, Itk-/-, and Rlk-/- x Itk-/- mice have defects in signaling and development, we asked whether Itk or Rlk function in actin polymerization at the immune synapse. We find that Itk-/- and Rlk-/- x Itk-/- T cells are defective in actin polymerization and conjugate formation in response to antigen-pulsed APCs. Itk functions downstream of the TCR, since similar defects were observed upon TCR engagement alone. Using conformation-specific probes, we show that although the recruitment of WASP and Arp2/3 complex to the immune synapse proceeds normally, the localized activation of Cdc42 and WASP is defective. Finally, we find that the defect in Cdc42 activation likely stems from a requirement for Itk in the recruitment of Vav to the immune synapse. Our results identify Itk as a key element of the pathway leading to localized actin polymerization at the immune synapse.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism*
  • Animals
  • Antigen-Presenting Cells / immunology*
  • Cell Cycle Proteins*
  • Enzyme Activation
  • Immunity / physiology
  • Mice
  • Microscopy, Fluorescence
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-vav
  • Spleen / cytology
  • T-Lymphocytes / immunology*
  • Wiskott-Aldrich Syndrome Protein
  • cdc42 GTP-Binding Protein / metabolism*


  • Actins
  • Cell Cycle Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • Vav1 protein, mouse
  • Was protein, mouse
  • Wiskott-Aldrich Syndrome Protein
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase
  • cdc42 GTP-Binding Protein