Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein.
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.
de Noronha
Sofia
S
Molecular Immunology Unit, Institute of Child Health, London WC1N 1EH, UK.
Hardy
Samantha
S
Sinclair
Joanna
J
Blundell
Michael P
MP
Strid
Jessica
J
Schulz
Oliver
O
Zwirner
Jörg
J
Jones
Gareth E
GE
Katz
David R
DR
Kinnon
Christine
C
Thrasher
Adrian J
AJ
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
C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D011506:Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D010081:Oxazolone