Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 77, Issue 6, Pages 993-998Publisher
WILEY
DOI: 10.1189/jlb.0804444
Keywords
primary immunodeficiency; Wiskott-Aldrich syndrome; gene therapy; chemokines
Categories
Funding
- NHLBI NIH HHS [HL59561] Funding Source: Medline
- NIAID NIH HHS [AI50950] Funding Source: Medline
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Intact cellular migration is critically important for the induction and regulation of the immune response. The Wiskott-Aldrich syndrome protein (WASP) regulates surface receptor signaling to die actin cytoskeleton in hematopoietic cells and thus plays a pivotal role in cellular locomotion. WASP deficiency causes the Wiskott-Aldrich. syndrome (WAS), characterized by inuminodeficiency, thrombocytopenia, and eczema. Cell migration defects may contribute to the pathophysiology of WAS. In this study, we used a variety of in vitro and in vivo assays to comprehensively analyze migration properties of lymphocytes, dendritic cells (DC), and neutrophils from WASP-deficient mice. We provide evidence that WASP-deficient lymphocytes show a marked reduction in tethering in an in vitro flow chamber assay as well as decreased migration of T cells in response to die CC chemokine ligand 19 (CCL19). In vivo, compared with wild-type lymphocytes, WASP-deficient lymphocytes showed significantly impaired homing to Pever's patches upon adoptive transfer into recipient mice. In addition, bone marrow-derived DC migrated less efficiently in response to CCL19. In vivo studies showed decreased migration of DC from skin to draining lymph nodes in WASP-deficient animals. Finally, we also document decreased neutroplil migration in vitro and hi vivo. In summary, our studies suggest that WASP plays an important role in the locomotion of lymphocytes, DC, and granulocytes in vitro and in vivo and thus, reveal a crucial role of WASP in physiological trafficking of various hematopoietic cell lineages. These results further delineate immunological abnormalities in WASP-deficient mice, which will be useful to assess preclinical gene therapy studies.
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