Wiskott-Aldrich syndrome protein and the cytoskeletal dynamics of dendritic cells

The regulated migration and spatial localization of dendritic cells in response to environmental signals are critical events during the initiation of physiological immune responses and maintenance of tolerance. Cells deficient in the Wiskott-Aldrich syndrome protein (WASP) have been used to demonstrate the importance of the dynamic remodelling of the actin-based cytoskeleton during the selective adhesion and migration of these cells. Unlike most cell types, macrophages, dendritic cells, and osteoclasts utilize a specialized adhesive array termed the podosome in order to migrate. Podosomes are composed of many of the same structural and regulatory proteins as seen in the more commonly found focal adhesion, but are unique in their requirement for WASP. Without WASP, podosomes cannot form and the affected cells are obliged to use focal adhesions for their migratory activities. Once activated by a series of upstream regulatory proteins, WASP acts as a scaffold for the binding of the potent actin nucleating protein complex known as Arp2/3. This article reviews the available evidence that suggests that failures in the regulation of the actin cytoskeleton may contribute significantly to the immunopathology of the Wiskott-Aldrich syndrome. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.