The Constant Region of the Membrane Immunoglobulin Mediates B Cell-Receptor Clustering and Signaling in Response to Membrane Antigens

Tolar, Pavel; Hanna, Joseph; Krueger, P.; Pierce, Susan K.

doi:10.1016/j.immuni.2008.11.007

Cited by 215 publications

(351 citation statements)

References 54 publications

(85 reference statements)

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“…We thus measured expression of the B cell surface activation marker CD69, which is significantly increased upon Ag recognition by the BCRs as indicated in published studies (23)(24)(25)34). In contrast to activation of Syk, the activation of CD69 takes place at the late stage of the BCR signaling transduction cascade, with a response occurring at the mRNA level through changes in the gene expression profile.…”

Section: The Mechanosensing Ability Of B Cells Affects Downstream B Cmentioning

confidence: 99%

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

110

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B lymphocytes are activated upon Ag sensing by BCRs. The substrate presenting the Ag can show different degrees of stiffness. It is not clear whether B cells can respond to changes in substrate stiffness. In this study we use high-resolution, high-speed live cell imaging techniques to capture the molecular events in B cell activation after the recognition of Ags tethered to polyacrylamide gel substrates with variable degrees of stiffness as quantified by Young’s modulus (2.6–22.1 kPa). We show that the initiation of B cell activation is extremely sensitive to substrate stiffness. B cells exhibit much stronger activation responses when encountering Ags tethered to substrates with a high degree of stiffness as measured by the accumulation of BCR, phospho-spleen tyrosine kinase, and phosphotyrosine molecules into the B cell immunological synapse. Ags tethered to stiff substrates induce the formation of more prominent BCR and phospho-spleen tyrosine kinase microclusters with significantly enhanced colocalization as compared with Ags tethered to soft substrates. Moreover, the expression of the B cell activation marker CD69 is enhanced in B cells encountering Ags on stiffer substrates. Through time-lapse live cell imaging, we find that the different responses of B cells to substrate stiffness are only demonstrated 5 min after BCR and Ag recognition. Using a series of cytoskeleton inhibitors, we determine that the mechanosensing ability of B cells is dependent on microtubules, and only mildly linked to the actin cytoskeleton. These results suggest the importance of the mechanical properties mediated by substrate stiffness in B cell activation.

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Section: The Mechanosensing Ability Of B Cells Affects Downstream B Cmentioning

confidence: 99%

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

110

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“…Lymphocyte activation is then driven by the transient interaction of downstream signalling intermediates with receptor microclusters, which is dependent on intact upstream signalling (Bunnell et al, 2002;Varma et al, 2006;Weber et al, 2008;Yokosuka et al, 2005). In fact, any interference with microcluster formation or stability rapidly attenuates signal transduction and blocks lymphocyte activation (Ilani et al, 2009;Tolar et al, 2009;Varma et al, 2006;Weber et al, 2008). Together with the requirement for nanoclusters in growth-factor signalling, these data underscore the importance of macromolecule clustering for proper cell function.…”

Section: Receptor and Signalling Microclusters In Lymphocytesmentioning

confidence: 99%

“…TIRF microscopy, a method for imaging fluorescence near the optical glass surface, has improved the level of detail that can be observed at the IS (see below) by reducing out-of-focus noise, and has led to the demonstration of microclusters containing TCRs or BCRs and downstream signalling intermediates in activated lymphocytes (Bunnell et al, 2002;Campi et al, 2005;Depoil et al, 2008;Tolar et al, 2009;Yokosuka et al, 2005). Such microclusters are assembled on the surface of lymphocytes within seconds of forming contact with an activating surface.…”

Section: Receptor and Signalling Microclusters In Lymphocytesmentioning

confidence: 99%

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Signalling complexes and clusters: functional advantages and methodological hurdles

Cebecauer

Spitaler

Sergé

et al. 2010

Journal of Cell Science

122

121

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SummarySignalling molecules integrate, codify and transport information in cells. Organisation of these molecules in complexes and clusters improves the efficiency, fidelity and robustness of cellular signalling. Here, we summarise current views on how signalling molecules assemble into macromolecular complexes and clusters and how they use their physical properties to transduce environmental information into a variety of cellular processes. In addition, we discuss recent innovations in live-cell imaging at the sub-micrometer scale and the challenges of object (particle) tracking, both of which help us to observe signalling complexes and clusters and to examine their dynamic character.

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“…The C-terminal tail of Cx43 is required for sustained BCR-mediated Rap1 activation and B-cell spreading J558 plasmacytoma cells, stably transfected with Ig and Ig so that they express a functional BCR on the cell surface (J558 m3), have been used to assay both the biochemical and structural requirements for BCR signaling (Flaswinkel and Reth, 1994;Tolar et al, 2009). J558 m3 cells do not spread radially like WEHI 231 cells (supplementary material Fig.…”

Section: Cx43 Expression Is Necessary For Bcr-mediated B-cell Spreadingmentioning

confidence: 99%

The gap junction protein Cx43 regulates B-lymphocyte spreading and adhesion

Machtaler

Dang-Lawson

Choi

et al. 2011

Journal of Cell Science

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SummaryThe gap junction protein connexin43 (Cx43) is widely expressed in mammalian cells and forms intercellular channels for the transfer of small molecules between adjacent cells, as well as hemichannels that mediate bidirectional transport of molecules between the cell and the surrounding environment. Cx43 regulates cell adhesion and migration in neurons and glioma cells, and we now show that Cx43 influences BCR-, LFA-1-and CXCL12-mediated activation of the Rap1 GTPase. Using shRNA knockdown of Cx43 in WEHI 231 cells, we show that Cx43 is required for sustained Rap1 activation and BCR-mediated spreading. To determine the domains of Cx43 that are important for this effect, Cx43-null J558 m3 B cells (which express a wild-type IgM BCR) were transfected with wildtype Cx43-GFP or a C-terminal-truncated Cx43 (Cx43T-GFP). Expression of wild-type Cx43-GFP, but not Cx43T-GFP, was sufficient to restore sustained, BCR-mediated Rap1 activation and cell spreading. Cx43, and specifically the C-terminal domain, was also important for LFA-1-and CXCL12-mediated Rap1 activation, spreading and adhesion to an endothelial cell monolayer. These data show that Cx43 has an important and previously unreported role in B-cell processes that are essential to normal B-cell development and immune responses.

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The Constant Region of the Membrane Immunoglobulin Mediates B Cell-Receptor Clustering and Signaling in Response to Membrane Antigens

Cited by 215 publications

References 54 publications

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Signalling complexes and clusters: functional advantages and methodological hurdles

The gap junction protein Cx43 regulates B-lymphocyte spreading and adhesion

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