A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival

J Exp Med. 2010 Apr 12;207(4):837-53. doi: 10.1084/jem.20091489. Epub 2010 Mar 22.

Abstract

Rac1 and Rac2 GTPases transduce signals from multiple receptors leading to cell migration, adhesion, proliferation, and survival. In the absence of Rac1 and Rac2, B cell development is arrested at an IgD- transitional B cell stage that we term transitional type 0 (T0). We show that T0 cells cannot enter the white pulp of the spleen until they mature into the T1 and T2 stages, and that this entry into the white pulp requires integrin and chemokine receptor signaling and is required for cell survival. In the absence of Rac1 and Rac2, transitional B cells are unable to migrate in response to chemokines and cannot enter the splenic white pulp. We propose that loss of Rac1 and Rac2 causes arrest at the T0 stage at least in part because transitional B cells need to migrate into the white pulp to receive survival signals. Finally, we show that in the absence of Syk, a kinase that transduces B cell antigen receptor signals required for positive selection, development is arrested at the same T0 stage, with transitional B cells excluded from the white pulp. Thus, these studies identify a novel developmental checkpoint that coincides with B cell positive selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Antigens, CD / metabolism
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Cell Adhesion / genetics
  • Cell Adhesion / immunology
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / immunology
  • Cell Movement* / drug effects
  • Cell Proliferation
  • Cell Survival / genetics
  • Chemokines / pharmacology
  • Immunoglobulin D / metabolism
  • Integrins / antagonists & inhibitors
  • Integrins / immunology
  • Integrins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Neuropeptides / genetics
  • Pertussis Toxin / pharmacology
  • Protein-Tyrosine Kinases / genetics
  • Proto-Oncogene Proteins c-vav / genetics
  • RAC2 GTP-Binding Protein
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, Chemokine / antagonists & inhibitors
  • Receptors, Chemokine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Spleen / cytology*
  • Spleen / immunology
  • Syk Kinase
  • bcl-X Protein / genetics
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • Antibodies
  • Antigens, CD
  • Bcl2l1 protein, mouse
  • CXCR4 protein, mouse
  • Chemokines
  • Immunoglobulin D
  • Integrins
  • Intracellular Signaling Peptides and Proteins
  • Lymphocyte Function-Associated Antigen-1
  • Neuropeptides
  • Proto-Oncogene Proteins c-vav
  • Rac1 protein, mouse
  • Receptors, CXCR4
  • Receptors, Chemokine
  • bcl-X Protein
  • Pertussis Toxin
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rap1 GTP-Binding Proteins