title: Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein.
abstract: Regulated migration and spatial localization of dendritic cells (DCs) are critical events during the initiation of physiologic immune responses and maintenance of tolerance. Here we have used cells deficient in the Wiskott-Aldrich syndrome protein (WASp) to demonstrate the importance of dynamic remodeling of the actin cytoskeleton for these trafficking processes to occur in vitro and in vivo. On fibronectin-coated surfaces, WASp-null immature murine DCs exhibited defects both of attachment and detachment, resulting in impaired net translocation compared with normal cells. The chemokinetic response to CCL21, which is critical for normal lymphatic trafficking, was also abrogated in the absence of WASp. In vivo in both fluorescein isothiocyanate (FITC) and oxazolone contact hypersensitivity models, WASp-null Langerhans cell (LC) migration was compromised, as judged by exit from the skin as well as by homing to the draining lymph node (LN). Furthermore, following systemic challenge with lipopolysaccharide (LPS) or toxoplasma-derived antigen, WASp-null DCs showed incomplete redistribution to T-cell areas in the spleen. Instead, they were retained ectopically in the marginal zone. DC trafficking in vivo is therefore dependent on a normally regulated actin cytoskeleton, which performs an essential function during maintenance of physiologic immunity and when disturbed may contribute significantly to the immunopathology of Wiskott-Aldrich Syndrome.
authors.affiliation: Molecular Immunology Unit, Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: de Noronha
authors.forename: Samantha
authors.initials: S
authors.lastname: Hardy
authors.forename: Joanna
authors.initials: J
authors.lastname: Sinclair
authors.forename: Michael P
authors.initials: MP
authors.lastname: Blundell
authors.forename: Jessica
authors.initials: J
authors.lastname: Strid
authors.forename: Oliver
authors.initials: O
authors.lastname: Schulz
authors.forename: Jörg
authors.initials: J
authors.lastname: Zwirner
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: David R
authors.initials: DR
authors.lastname: Katz
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000494:pharmacology; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology*; D003877:Dermatitis, Contact / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D007801:Langerhans Cells / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010081:Oxazolone / Q000008:administration & dosage / Q000276:immunology; D011506:Proteins / Q000235:genetics*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D011506:Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D010081:Oxazolone