title: Itk controls the spatiotemporal organization of T cell activation.
abstract: During T cell activation by antigen-presenting cells (APCs), the diverse spatiotemporal organization of components of T cell signaling pathways modulates the efficiency of activation. Here, we found that loss of the tyrosine kinase interleukin-2 (IL-2)-inducible T cell kinase (Itk) in mice altered the spatiotemporal distributions of 14 of 16 sensors of T cell signaling molecules in the region of the interface between the T cell and the APC, which reduced the segregation of signaling intermediates into distinct spatiotemporal patterns. Activation of the Rho family guanosine triphosphatase Cdc42 at the center of the cell-cell interface was impaired, although the total cellular amount of active Cdc42 remained intact. The defect in Cdc42 localization resulted in impaired actin accumulation at the T cell-APC interface in Itk-deficient T cells. Reconstitution of cells with active Cdc42 that was specifically directed to the center of the interface restored actin accumulation in Itk-deficient T cells. Itk also controlled the central localization of the guanine nucleotide exchange factor SLAT [Switch-associated protein 70 (SWAP-70)-like adaptor of T cells], which may contribute to the activation of Cdc42 at the center of the interface. Together, these data illustrate how control of the spatiotemporal organization of T cell signaling controls critical aspects of T cell function.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kentner L
authors.initials: KL
authors.lastname: Singleton
authors.forename: Monica
authors.initials: M
authors.lastname: Gosh
authors.forename: Radhika D
authors.initials: RD
authors.lastname: Dandekar
authors.forename: Byron B
authors.initials: BB
authors.lastname: Au-Yeung
authors.forename: Olga
authors.initials: O
authors.lastname: Ksionda
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Fowell
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000199:Actins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein; C473249:Def6 protein, mouse; C080813:emt protein-tyrosine kinase