Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor

Freeman, Spencer A.; Jaumouillé, Valentin; Choi, Kate; Hsu, Brian; Wong, Ho-Lun; Abraham, Libin; Graves, Marcia L.; Coombs, Daniel; Roskelley, Calvin D.; Das, Raj Kumar; Grinstein, Sergio; Gold, Michael R.

doi:10.1038/ncomms7168

Cited by 76 publications

(92 citation statements)

References 70 publications

(139 reference statements)

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“…An example is the synergy between BCR and Toll-like receptor (TLR) signalling. TLR engagement increases BCR sensitivity to antigen and this depends on increased BCR diffusion and clustering induced by elevated severing activity of cofilin 155 . Interestingly, enhanced responsiveness to both TLR ligands and antigen in WAS-deficient B cells promotes the selection of autoreactive specificities in transitional B cells 6 , and leads to loss of marginal zone B cells 156 .…”

Section: [H1] Cytoskeletal Regulation Of B Cell Subsetsmentioning

confidence: 99%

“…Interestingly, enhanced responsiveness to both TLR ligands and antigen in WAS-deficient B cells promotes the selection of autoreactive specificities in transitional B cells 6 , and leads to loss of marginal zone B cells 156 . TLR-induced activation of cofilin may also be involved in the enhanced antigen reactivity of normal marginal zone B cells 155 . Thus, changes in cytoskeletal activity can have different effects on the responsiveness of specific B cell subsets.…”

Section: [H1] Cytoskeletal Regulation Of B Cell Subsetsmentioning

confidence: 99%

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Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

123

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The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton couples extensively to B cell receptor (BCR) signalling pathways and its defects can either enhance or suppress B cell activation. Recent insights from single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion, and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also play a role in the adaptation of B cell subsets to specialized tasks during antibody responses.3

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Section: [H1] Cytoskeletal Regulation Of B Cell Subsetsmentioning

confidence: 99%

Section: [H1] Cytoskeletal Regulation Of B Cell Subsetsmentioning

confidence: 99%

Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

123

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“…3E,F). These peptides prevent endogenous cofilin from binding to and severing actin filaments (Eibert et al, 2004), and thereby inhibit actin dynamics in B cells (Freeman et al, 2015). MTOC polarization occurred normally in the presence of the control Q peptide in which key residues in the W peptide were changed so as to ablate F-actin binding.…”

Section: Mtoc Polarization Requires Cofilin-mediated Actin Severingmentioning

confidence: 99%

“…To assess the role of cofilin-mediated F-actin severing in MTOC polarization, A20 cells were transiently transfected with mCherry-tagged wild-type (WT) cofilin, or with a cofilin mutant that had a phosphomimetic S→D mutation at S3. This S3D mutant, which acts in a dominant-negative manner to prevent BCR-induced actin reorganization (Freeman et al, 2015(Freeman et al, , 2011, blocked MTOC polarization towards anti-Ig-coated beads (Fig. 3C,D).…”

Section: Mtoc Polarization Requires Cofilin-mediated Actin Severingmentioning

confidence: 99%

“…Initial BCR signaling at the B-cell-APC interface promotes disassembly of the submembrane actin network and uncouples the actin meshwork from the plasma membrane (Freeman et al, 2011;Treanor et al, 2011Treanor et al, , 2010. This increases BCR mobility (Freeman et al, 2015;Treanor et al, 2010), allowing antigen-bound BCRs to form microclusters that recruit signaling enzymes Tolar et al, 2009;Treanor et al, 2009). Concomitant actin polymerization at the cell periphery allows the B cell to spread across the antigen-bearing surface, encounter more antigens, and form additional BCR microclusters (Fleire et al, 2006;Song et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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The Rap1–cofilin-1 pathway coordinates actin reorganization and MTOC polarization at the B cell immune synapse

Wang

Lee

Christian

et al. 2017

Journal of Cell Science

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B cells that bind antigens displayed on antigen-presenting cells (APCs) form an immune synapse, a polarized cellular structure that optimizes the dual functions of the B cell receptor (BCR), signal transduction and antigen internalization. Immune synapse formation involves polarization of the microtubule-organizing center (MTOC) towards the APC. We now show that BCR-induced MTOC polarization requires the Rap1 GTPase (which has two isoforms, Rap1a and Rap1b), an evolutionarily conserved regulator of cell polarity, as well as cofilin-1, an actin-severing protein that is regulated by Rap1. MTOC reorientation towards the antigen contact site correlated strongly with cofilin-1-dependent actin reorganization and cell spreading. We also show that BCR-induced MTOC polarization requires the dynein motor protein as well as IQGAP1, a scaffolding protein that can link the actin and microtubule cytoskeletons. At the periphery of the immune synapse, IQGAP1 associates closely with Factin structures and with the microtubule plus-end-binding protein CLIP-170 (also known as CLIP1). Moreover, the accumulation of IQGAP1 at the antigen contact site depends on F-actin reorganization that is controlled by Rap1 and cofilin-1. Thus the Rap1-cofilin-1 pathway coordinates actin and microtubule organization at the immune synapse.

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Molecular cues involved in the regulation of B cell dynamics: Assistants of antigen hunting

Carrasco

2020

Journal of Leukocyte Biology

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The ability of a cell to migrate, adhere, and change its morphology is determinant in developing its functions; these capacities reach their maximum relevance in immune cells. For an efficient immune response, immune cells must localize in the right place at the right time; that implies crossing tissue barriers and migrating in the interstitial space of the tissues at high velocities. The dependency on trafficking abilities is even higher for B cells, one of the arms of the adaptive immune system, considering that they must encounter specific antigens for their clonal receptor in the enormous tissue volume of the secondary lymphoid organs (spleen, lymph nodes, Peyer patches). The regulated interplay between cell motility and cell adhesion allows B cells to reach distinct lymphoid tissues and, within them, to explore the stromal cell networks where antigen might be exposed. In this meeting‐invited review, I summarize the current knowledge on the molecular cues and mechanisms that shapes B cell dynamics at the initial phase of the humoral immune response, including homeostatic chemoattractants and innate/inflammatory stimuli. I also revised the B cell behavior alterations caused by BCR recognition of antigen and the molecular mechanisms involved.

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Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor

Cited by 76 publications

References 70 publications

Cytoskeletal control of B cell responses to antigens

Cytoskeletal control of B cell responses to antigens

The Rap1–cofilin-1 pathway coordinates actin reorganization and MTOC polarization at the B cell immune synapse

Molecular cues involved in the regulation of B cell dynamics: Assistants of antigen hunting

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