Itk Functions to Control Actin Polymerization at the Immune Synapse through Localized Activation of Cdc42 and WASP

• DOI: 10.1016/j.cub.2003.08.005
• Publication Date: 2003-09-22T19:26:20Z
• Authors: Christine M. Labno; Carol M. Lewis; Daoqi You; Daisy W. Leung; Ana Takesono; Natalie Kamberos; Abhinav Seth; Lisa D. Finkelstein; Michael K. Rosen; Pamela L. Schwart...; Janis K. Burkhardt
• Keywords: Immunological synapse; CDC42; Wiskott–Aldrich syndrome protein

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.