title: The Wiskott-Aldrich syndrome protein permits assembly of a focused immunological synapse enabling sustained T-cell receptor signaling.
abstract: BACKGROUND
  T-cell activation relies on the assembly of the immunological synapse, a structure tightly regulated by the actin cytoskeleton. The precise role of the Wiskott-Aldrich syndrome protein, an actin cytoskeleton regulator, in linking immunological synapse structure to downstream signaling remains to be clarified.
  
  
  METHODS
  To address this point, CD4(+) T cells from patients with Wiskott-Aldrich syndrome were stimulated with antigen-presenting cells. The structure and dynamics of the immunological synapse were studied by confocal and video-microscopy.
  
  
  RESULTS
  Upon stimulation by antigen-presenting cells, Wiskott-Aldrich syndrome protein-deficient T cells displayed reduced cytokine production and proliferation. Although Wiskott-Aldrich syndrome T cells formed conjugates with antigen-presenting cells at normal frequency and exhibited normal T-cell receptor down-regulation, they emitted actin-rich protrusions away from the immunological synapse area and their microtubule organizing center failed to polarize fully towards the center of the immunological synapse. In parallel, abnormally dispersed phosphotyrosine staining revealed unfocused synaptic signaling in Wiskott-Aldrich syndrome T cells. Time-lapse microscopy confirmed the anomalous morphology of Wiskott-Aldrich syndrome T-cell immunological synapses and showed erratic calcium mobilization at the single-cell level.
  
  
  CONCLUSIONS
  Taken together, our data show that the Wiskott-Aldrich syndrome protein is required for the assembly of focused immunological synapse structures allowing optimal signal integration and sustained calcium signaling.
authors.affiliation: INSERM, U1043, Toulouse, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Calvez
authors.forename: Fanny
authors.initials: F
authors.lastname: Lafouresse
authors.forename: Julie
authors.initials: J
authors.lastname: De Meester
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valitutti
authors.forename: Loïc
authors.initials: L
authors.lastname: Dupré
mesh_terms: D000938:Antigen-Presenting Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D006801:Humans; D054992:Immunological Synapses / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D018089:Superantigens / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D051316:Wiskott-Aldrich Syndrome Protein; D002118:Calcium