IntroductionDendritic cells (DCs) are highly motile bone marrow-derived antigen-presenting cells (APCs). They have specialized migratory and homing properties that allow them both to initiate primary immune responses and to induce tolerance. 1,2 In lymphoid organs they are present as interdigitating cells in the white pulp of the spleen and in the paracortex of lymph nodes (LNs) where they are able to capture incoming foreign antigen from blood or lymph, respectively. In nonlymphoid tissues DCs act as sentinels of injury and patrol for the presence of foreign antigens and pathogens. Upon capture they migrate to draining secondary lymphoid tissue during which time they mature and develop the capacity to stimulate antigen specific T cells.The migration and spatial localization of DCs are controlled by numerous extrinsic factors, including chemokine family members to which they are responsive through maturation and localizationdependent mechanisms. [3][4][5][6][7] The physical motility of cells and anchorage in specific tissues is, however, ultimately dependent on the regulated dynamics of the actin cytoskeleton, which determines the response of cells to chemokine gradients and enables purposeful movement through the sequential process of leading-edge protrusion, attachment, and tail retraction. 8 The molecular control of this highly coordinated activity is orchestrated by Rho family guanosine triphosphatases (GTPases), the best characterized of which are Cdc42, Rac1/2, and RhoA, and their downstream effectors. 9 In hematopoietic cells, a key effector for Cdc42 is the Wiskott-Aldrich syndrome protein (WASp). WASp is a 502-amino acid member of a conserved family of proteins that participate in the organization of actin polymerization primarily through activation of the actin-related protein (Arp2/Arp3) complex. [10][11][12] Interference in these signaling pathways results in multiple cytoskeletal defects in DCs, including the failure to form normal membrane projections and specialized structures known as podosomes, which form behind the leading edge of motile cells. [13][14][15][16] Podosomes concentrate ␤2 integrins around an actin core and, although their function has not been clearly identified, are responsible for tight adhesion of cells to intercellular adhesion molecule-1 (ICAM-1) and possibly junctional adhesion molecule-A (JAM-A). [17][18][19] Furthermore, they are highly dynamic with a turnover of minutes, providing a migrating cell with a mechanism for rapid attachment and detachment, and with localized anchorage points that could facilitate traverse of endothelial barriers in particular.Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, eczema, and autoimmunity. 12 The pathophysiology of WAS relates to defective polymerization of [20][21][22][23][24][25][26] However, defects of migration identified in myeloid and T cells in vitro, and stem cells in vivo, [27][28][29][30][31] all support the hypothesis that many of the immunologic consequences of WASp deficiency ar...