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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4139-4147.
Prepublished online as a Blood First Edition Paper on September 4, 2008; DOI 10.1182/blood-2008-02-140715.
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Submitted February 25, 2008
Accepted July 23, 2008
WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function
Lisa Westerberg, Miguel A. de la Fuente, Fredrik Wermeling, Hans D. Ochs, Mikael C.I. Karlsson, Scott B. Snapper, and Luigi D. Notarangelo*
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston
Immunology, Children's Hospital, Harvard Medical School, Boston
Medicine, Karolinska Institute, Stockholm
Pediatrics, University of Washington, Seattle
Medicine, Harvard Medical School, Massachusetts General Hospital, Boston
Pediatrics, Harvard Medical School, Boston
* Corresponding author; email: luigi.notarangelo{at}childrens.harvard.edu.
Development of hematopoietic cells depends on a dynamic actin cytoskeleton. Here we demonstrate that expression of the cytoskeletal regulator WASP, mutated in the Wiskott-Aldrich syndrome, provides selective advantage for the development of naturally occurring regulatory T cells, natural killer T cells, CD4+ and CD8+ T lymphocytes, marginal zone (MZ) B cells, MZ macrophages, and platelets. To define the relative contribution of MZ B cells and MZ macrophages for MZ development, we generated wild-type and WASP-deficient bone marrow chimeric mice, with full restoration of the MZ. However, even in the presence of MZ macrophages, only 10% of MZ B cells were of WASP-deficient origin. We show that WASP-deficient MZ B cells hyperproliferate in vivo and fail to respond to sphingosine-1-phosphate, a crucial chemoattractant for MZ B cell positioning. Abnormalities of the MZ compartment in WASP-/- mice lead to aberrant uptake of S. aureus and to a reduced immune response to TNP-Ficoll. Moreover, WASP-deficient mice have increased levels of "natural" IgM antibodies. Our findings reveal that WASP regulates both development and function of hematopoietic cells. We demonstrate that WASP-deficiency leads to an aberrant MZ that may affect responses to blood borne pathogens and peripheral B cell tolerance.
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