title: WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function.
abstract: 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 Staphylococcus 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.
authors.affiliation: Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston, USA.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
authors.forename: Miguel A
authors.initials: MA
authors.lastname: de la Fuente
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wermeling
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Mikael C I
authors.initials: MC
authors.lastname: Karlsson
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002630:Chemotactic Factors / Q000276:immunology / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D008246:Lysophospholipids / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology*
chemical_list: D002630:Chemotactic Factors; D007075:Immunoglobulin M; D008246:Lysophospholipids; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C060506:sphingosine 1-phosphate; D013110:Sphingosine
references.citation: J Pediatr. 1994 Dec;125(6 Pt 1):876-85
references.pmid: 7996359
references.citation: Clin Exp Immunol. 2005 Feb;139(2):297-305
references.pmid: 15654828
references.citation: Nat Immunol. 2008 Jan;9(1):54-62
references.pmid: 18037889
references.citation: Blood. 2003 Aug 15;102(4):1282-9
references.pmid: 12730112
references.citation: Blood. 2002 Aug 15;100(4):1208-14
references.pmid: 12149199
references.citation: Expert Opin Biol Ther. 2008 Feb;8(2):181-90
references.pmid: 18194074
references.citation: J Exp Med. 2003 Jul 21;198(2):333-40
references.pmid: 12874264
references.citation: Immunol Rev. 2004 Feb;197:192-205
references.pmid: 14962196
references.citation: Nat Rev Immunol. 2005 Aug;5(8):606-16
references.pmid: 16056254
references.citation: Blood. 2001 Mar 15;97(6):1598-603
references.pmid: 11238097
references.citation: Blood. 2003 Mar 15;101(6):2159-66
references.pmid: 12433691
references.citation: Blood. 1995 May 1;85(9):2471-7
references.pmid: 7537115
references.citation: J Exp Med. 2007 Feb 19;204(2):369-80
references.pmid: 17296785
references.citation: J Clin Immunol. 2007 Nov;27(6):634-9
references.pmid: 17690954
references.citation: Curr Opin Hematol. 2008 Jan;15(1):30-6
references.pmid: 18043243
references.citation: Annu Rev Immunol. 2007;25:297-336
references.pmid: 17150027
references.citation: Blood. 2004 Sep 1;104(5):1270-2
references.pmid: 15142877
references.citation: Immunity. 1995 Sep;3(3):283-99
references.pmid: 7552994
references.citation: J Leukoc Biol. 2005 Jun;77(6):993-8
references.pmid: 15774550
references.citation: Gene Ther. 2007 Mar;14(5):415-28
references.pmid: 17051251
references.citation: Blood. 2007 Dec 15;110(13):4278-84
references.pmid: 17673604
references.citation: Annu Rev Immunol. 2005;23:161-96
references.pmid: 15771569
references.citation: Br J Haematol. 1998 Jun;101(4):659-65
references.pmid: 9674738
references.citation: Immunity. 1998 Jul;9(1):81-91
references.pmid: 9697838
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15424-9
references.pmid: 17878299
references.citation: Immunity. 2003 May;18(5):675-85
references.pmid: 12753744
references.citation: Clin Immunol. 2007 Jul;124(1):41-8
references.pmid: 17512803
references.citation: J Immunol. 2004 Mar 15;172(6):3620-7
references.pmid: 15004164
references.citation: Blood. 2004 Dec 1;104(12):3454-62
references.pmid: 15308573
references.citation: Blood. 1997 Oct 1;90(7):2680-9
references.pmid: 9326235
references.citation: Blood. 2005 Feb 15;105(4):1590-7
references.pmid: 15494425
references.citation: Bone Marrow Transplant. 2006 Nov;38(10):671-9
references.pmid: 17013426
references.citation: Blood. 2003 Nov 1;102(9):3108-16
references.pmid: 12855574
references.citation: Science. 2002 Jul 19;297(5580):409-12
references.pmid: 12130787
references.citation: J Exp Med. 2007 Feb 19;204(2):381-91
references.pmid: 17296786
references.citation: J Exp Med. 2007 Oct 1;204(10):2259-65
references.pmid: 17893199
references.citation: Blood. 2005 Feb 1;105(3):1144-52
references.pmid: 15383456
references.citation: Am J Surg Pathol. 1999 Feb;23(2):182-91
references.pmid: 9989845
references.citation: Science. 1993 Jul 16;261(5119):358-61
references.pmid: 8332901
references.citation: Annu Rev Immunol. 2001;19:595-621
references.pmid: 11244048
references.citation: Expert Opin Biol Ther. 2007 Oct;7(10):1575-82
references.pmid: 17916049
references.citation: Blood. 2004 Jan 15;103(2):676-8
references.pmid: 14504083
references.citation: J Clin Invest. 2007 Feb;117(2):407-18
references.pmid: 17218989
references.citation: Nat Immunol. 2004 Jul;5(7):713-20
references.pmid: 15184895
references.citation: J Immunol. 2001 Apr 15;166(8):4831-4
references.pmid: 11290758
references.citation: Hum Gene Ther. 2002 Jun 10;13(9):1039-46
references.pmid: 12067437
references.citation: Blood. 2008 Jan 1;111(1):439-45
references.pmid: 17901250
references.citation: Exp Hematol. 2006 Sep;34(9):1161-9
references.pmid: 16939809
references.citation: J Immunol. 1998 Jul 15;161(2):1026-33
references.pmid: 9670984