title: Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming.
abstract: Rearrangement of the cytoskeleton in T cells plays a critical role in the organization of a complex signaling interface referred to as immunologic synapse (IS). Surprisingly, the contribution of antigen presenting cells, in particular dendritic cells (DCs), to the structure and function of the IS has not been investigated in as much detail. We have used a natural model of cytoskeletal dysfunction caused by deficiency of the Wiskott-Aldrich syndrome protein (WASp) to explore the contribution of the DC cytoskeleton to IS formation and to T-cell priming. In an antigen-specific system, T-DC contacts were found to be less stable when DCs alone lacked WASp, and associated with multiple defects of IS structure. As a consequence, DCs were unable to support normal IL-12 secretion, and events downstream of TCR signaling were abrogated, including increased calcium flux, microtubule organizing center (MTOC) polarization, phosphorylation of ZAP-70, and T-cell proliferation. Formation of an effective signaling interface is therefore dependent on active cytoskeletal rearrangements in DCs even when T cells are functionally competent. Deficiency of DC-mediated activities may contribute significantly to the varied immunodysregulation observed in patients with WAS, and also in those with limited myeloid reconstitution after allogeneic hematopoietic stem cell transplantation.
authors.affiliation: Molecular Immunology Unit, Centre for Immunodeficiency, University College London (UCL) Institute of Child Health, London, UK.
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.forename: Ariadna
authors.initials: A
authors.lastname: Mendoza-Naranjo
authors.forename: Michael P
authors.initials: MP
authors.lastname: Blundell
authors.forename: Elena
authors.initials: E
authors.lastname: de Falco
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsley
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000032:analysis / Q000235:genetics; D020013:Calcium Signaling / Q000276:immunology; D002465:Cell Movement; D003433:Crosses, Genetic; D003599:Cytoskeleton / Q000648:ultrastructure*; D003713:Dendritic Cells / Q000648:ultrastructure*; D017930:Genes, Reporter; D005816:Genetic Complementation Test; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology / Q000648:ultrastructure*; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C054562:yellow fluorescent protein, Bacteria; D010047:Ovalbumin