scholarly journals Entry of B Cell Receptor into Signaling Domains Is Inhibited in Tolerant B Cells

2000 ◽  
Vol 191 (8) ◽  
pp. 1443-1448 ◽  
Author(s):  
Bennett C. Weintraub ◽  
Jesse Eunsuk Jun ◽  
Anthony C. Bishop ◽  
Kevan M. Shokat ◽  
Matthew L. Thomas ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Tyrosine Phosphatase ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Calcium Flux ◽  
Homogeneous Population ◽  
Kinase Activation ◽  
Antigen Receptor Signaling

Signal transduction through the B cell antigen receptor (BCR) is altered in B cells that express a receptor that recognizes self-antigen. To understand the molecular basis for the change in signaling in autoreactive B cells, a transgenic model was used to isolate a homogeneous population of tolerant B lymphocytes. These cells were compared with a similar population of naive B lymphocytes. We show that the BCR from naive B cells enters a detergent-insoluble domain of the cell within 6 s after antigen binding, before a detectable increase in BCR phosphorylation. This fraction appears to be important for signaling because it is enriched for lyn kinase but lacks CD45 tyrosine phosphatase and because the BCR that moves into this domain becomes more highly phosphorylated. Partitioning of the BCR into this fraction is unaffected by src family kinase inhibition. Tolerant B cells do not efficiently partition the BCR into the detergent-insoluble domain, providing an explanation for their reduced tyrosine kinase activation and calcium flux in response to antigen. These results identify an early, regulated step in antigen receptor signaling and self-tolerance.

scholarly journals An extracatalytic function of CD45 in B cells is mediated by CD22

2015 ◽  
Vol 112 (47) ◽  
pp. E6515-E6524 ◽  
Author(s):  
Sarah Coughlin ◽  
Mark Noviski ◽  
James L. Mueller ◽  
Ammarina Chuwonpad ◽  
William C. Raschke ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Tyrosine Phosphatase ◽  
Antigen Receptor ◽  
Src Family Kinases ◽  
B Cell Antigen Receptor ◽  
T Cell Signaling ◽  
Antigen Receptor Signaling ◽  
Bcr Signaling ◽  
Alternatively Spliced

The receptor-like tyrosine phosphatase CD45 regulates antigen receptor signaling by dephosphorylating the C-terminal inhibitory tyrosine of the src family kinases. However, despite its abundance, the function of the large, alternatively spliced extracellular domain of CD45 has remained elusive. We used normally spliced CD45 transgenes either incorporating a phosphatase-inactivating point mutation or lacking the cytoplasmic domain to uncouple the enzymatic and noncatalytic functions of CD45 in lymphocytes. Although these transgenes did not alter T-cell signaling or development irrespective of endogenous CD45 expression, both partially rescued the phenotype of CD45-deficient B cells. We identify a noncatalytic role for CD45 in regulating tonic, but not antigen-mediated, B-cell antigen receptor (BCR) signaling through modulation of the function of the inhibitory coreceptor CD22. This finding has important implications for understanding how naïve B cells maintain tonic BCR signaling while restraining inappropriate antigen-dependent activation to preserve clonal “ignorance.”

scholarly journals SLP-65: A New Signaling Component in B Lymphocytes which Requires Expression of the Antigen Receptor for Phosphorylation

1998 ◽  
Vol 188 (4) ◽  
pp. 791-795 ◽  
Author(s):  
Jürgen Wienands ◽  
Jutta Schweikert ◽  
Bernd Wollscheid ◽  
Hassan Jumaa ◽  
Peter J. Nielsen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Antigen Receptor ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
B Cell Antigen Receptor ◽  
Signaling Complex ◽  
Membrane Bound

The B cell antigen receptor (BCR) consists of the membrane-bound immunoglobulin (Ig) molecule as antigen-binding subunit and the Ig-α/Ig-β heterodimer as signaling subunit. BCR signal transduction involves activation of protein tyrosine kinases (PTKs) and phosphorylation of several proteins, only some of which have been identified. The phosphorylation of these proteins can be induced by exposure of B cells either to antigen or to the tyrosine phosphatase inhibitor pervanadate/H2O2. One of the earliest substrates in B cells is a 65-kD protein, which we identify here as a B cell adaptor protein. This protein, named SLP-65, is part of a signaling complex involving Grb-2 and Vav and shows homology to SLP-76, a signaling element of the T cell receptor. In pervanadate/H2O2-stimulated cells, SLP-65 becomes phosphorylated only upon expression of the BCR. These data suggest that SLP-65 is part of a BCR transducer complex.

scholarly journals Induction of Cytosolic Calcium Flux by CD20 Is Dependent upon B Cell Antigen Receptor Signaling

2008 ◽  
Vol 283 (25) ◽  
pp. 16971-16984 ◽  
Author(s):  
Claire A. Walshe ◽  
Stephen A. Beers ◽  
Ruth R. French ◽  
Claude H. T. Chan ◽  
Peter W. Johnson ◽  
...  
Keyword(s):  
B Cell ◽  
Antigen Receptor ◽  
Cytosolic Calcium ◽  
Calcium Flux ◽  
B Cell Antigen Receptor ◽  
Receptor Signaling ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Antigen Receptor Signaling

The development of functional B lymphocytes in conditional PU.1 knock-out mice

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2083-2090 ◽  
Author(s):  
Matthew Polli ◽  
Aleksandar Dakic ◽  
Amanda Light ◽  
Li Wu ◽  
David M. Tarlinton ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Fetal Liver ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Knock Out ◽  
B Lineage ◽  
And Function

Abstract An abundance of research has entrenched the view that the Ets domain containing transcription factor PU.1 is fundamental to the development and function of B lymphocytes. In this study, we have made use of a conditional PU.1 allele to test this notion. Complete deletion of PU.1 resulted in the loss of B cells and all other lineage-positive cells in the fetal liver and death between E18.5 and birth; however, specific deletion of PU.1 in the B lineage had no effect on B-cell development. Furthermore, deletion of PU.1 in B cells did not compromise their ability to establish and maintain an immune response. An increased level of apoptosis was observed in vitro upon B-cell receptor (BCR) cross-linking; however, this was partially rescued by interleukin-4 (IL-4). These findings suggest that PU.1 is not essential for the development of functional B lymphocytes beyond the pre-B stage. (Blood. 2005;106:2083-2090)

scholarly journals Grb2 and GRAP connect the B cell antigen receptor to Erk MAP kinase activation in human B cells

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Kanika Vanshylla ◽  
Caren Bartsch ◽  
Christoffer Hitzing ◽  
Laura Krümpelmann ◽  
Jürgen Wienands ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Map Kinase ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
Kinase Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Human B Cells

scholarly journals B Lymphocyte Chemotaxis Regulated in Association with Microanatomic Localization, Differentiation State, and B Cell Receptor Engagement

1998 ◽  
Vol 187 (5) ◽  
pp. 753-762 ◽  
Author(s):  
Conrad C. Bleul ◽  
Joachim L. Schultze ◽  
Timothy A. Springer
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Messenger Rna ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cxc Chemokine

Migration of mature B lymphocytes within secondary lymphoid organs and recirculation between these sites are thought to allow B cells to obtain T cell help, to undergo somatic hypermutation, to differentiate into effector cells, and to home to sites of antibody production. The mechanisms that direct migration of B lymphocytes are unknown, but there is evidence that G protein–coupled receptors, and possibly chemokine receptors, may be involved. Stromal cell– derived factor (SDF)-1α is a CXC chemokine previously characterized as an efficacious chemoattractant for T lymphocytes and monocytes in peripheral blood. Here we show with purified tonsillar B cells that SDF-1α also attracts naive and memory, but not germinal center (GC) B lymphocytes. Furthermore, GC B cells could be converted to respond to SDF-1α by in vitro differentiation into memory B lymphocytes. Conversely, the migratory response in naive and memory B cells was significantly reduced after B cell receptor engagement and CD40 signaling. The receptor for SDF-1, CXC chemokine receptor 4 (CXCR4), was found to be expressed on responsive as well as unresponsive B cell subsets, but was more rapidly downregulated on responsive cells by ligand. Finally, messenger RNA for SDF-1 was detected by in situ hybridization in a layer of cells surrounding the GC. These findings show that responsiveness to the chemoattractant SDF-1α is regulated during B lymphocyte activation, and correlates with positioning of B lymphocytes within a secondary lymphoid organ.

scholarly journals Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity

2002 ◽  
Vol 196 (12) ◽  
pp. 1593-1604 ◽  
Author(s):  
Margaret L. Hibbs ◽  
Kenneth W. Harder ◽  
Jane Armes ◽  
Nicole Kountouri ◽  
Cathy Quilici ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Antigen Receptor ◽  
Calcium Flux ◽  
Genetic Ablation ◽  
Lyn Tyrosine Kinase ◽  
Constitutive Phosphorylation ◽  
Sustained Activation

Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles in B lymphocyte signaling. We now report the consequences of sustained activation of Lyn in vivo using a targeted gain-of-function mutation (Lynup/up mice). Lynup/up mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lynup/up B cells are characterized by the constitutive phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered tolerant by constitutive engagement of the antigen receptor. However, exaggerated positive signaling is also apparent as evidenced by the constitutive phosphorylation of Syk and phospholipase Cγ2 in resting Lynup/up B cells. Similarly, Lynup/up B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lynup/up mice develop circulating autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced positive signaling eventually overrides constitutive negative signaling. These studies highlight the difficulty in maintaining tolerance in the face of chronic stimulation and emphasize the pivotal role of Lyn in B cell signaling.

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