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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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Submitted June 18, 2004
Accepted October 3, 2004
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, Jorg Zwirner, Gareth E Jones, David R Katz, Christine Kinnon, and Adrian J Thrasher*
Molecular Immunology Unit, Institute of Child Health, London, United Kingdom
Immunobiology Unit, Institute of Child Health, London, United Kingdom
Immunobiology Laboratory, Cancer Research UK, London, United Kingdom
Department of Immunology, Georg-August-University Gottingen, Gottingen, Germany
The Randall Centre for Molecular Mechanisms of Cell Function, King's College London, London, United Kingdom
Department of Immunology, University College London, Windeyer Institute, London, United Kingdom
Molecular Immunology Unit, Institute of Child Health, London, United Kingdom; Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, United Kingdom
* Corresponding author; email: a.thrasher{at}ich.ucl.ac.uk.
Regulated migration and spatial localization of dendritic cells (DC) are critical events during the initiation of physiological 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 DC exhibited defects both of attachment and detachment resulting in impaired net translocation compared to 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 FITC and oxazolone contact hypersensitivity models WASp-null LC migration was compromised, as judged by exit from the skin as well as by homing to the draining LN. Furthermore, following systemic challenge with LPS or toxoplasma-derived antigen, WASp-null DC 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 physiological immunity, and when disturbed may contribute significantly to the immunopathology of the Wiskott-Aldrich Syndrome.
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