WASP deficiency leads to global defects of directed leukocyte migration in vitro and in vivo.
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 the actin cytoskeleton in hematopoietic cells and thus plays a pivotal role in cellular locomotion. WASP deficiency causes the Wiskott-Aldrich syndrome (WAS), characterized by immunodeficiency, 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 the CC chemokine ligand 19 (CCL19). In vivo, compared with wild-type lymphocytes, WASP-deficient lymphocytes showed significantly impaired homing to Peyer'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 neutrophil migration in vitro and in 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.
Snapper
Scott B
SB
Gastrointestinal Unit and the Center for Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston, 02114, USA. ssnapper@partners.org
Meelu
Parool
P
Nguyen
Deanna
D
Stockton
Britt M
BM
Bozza
Patricia
P
Alt
Frederick W
FW
Rosen
Fred S
FS
von Andrian
Ulrich H
UH
Klein
Christoph
C
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D051316:Wiskott-Aldrich Syndrome Protein
C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D011506:Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein