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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1590-1597.
Prepublished online as a Blood First Edition Paper on October 19, 2004; DOI 10.1182/blood-2004-06-2332.
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IMMUNOBIOLOGY
Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein
Sofia de Noronha,
Samantha Hardy,
Joanna Sinclair,
Michael P. Blundell,
Jessica Strid,
Oliver Schulz,
Jörg Zwirner,
Gareth E. Jones,
David R. Katz,
Christine Kinnon, and
Adrian J. Thrasher
From the Molecular Immunology Unit, Institute of Child Health, London, United Kingdom; the Immunobiology Unit, Institute of Child Health, London, United Kingdom; the Immunobiology Laboratory, Cancer Research United Kingdom, Lincoln's Inn Fields Laboratories, London, United Kingdom; the Department of Immunology, Georg-August-University Göttingen, Germany; the Randall Centre for Molecular Mechanisms of Cell Function, King's College London, United Kingdom; the Department of Immunology, University College London, Windeyer Institute, United Kingdom; and the Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, United Kingdom.
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.
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