Key Points
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B cells form immunological synapses upon engagement of their B cell receptor (BCR) with antigen that is exposed at the surface of specialized presenting cells. Synapse formation promotes the extraction and the processing of immobilized antigens for presentation on MHC class II molecules to primed CD4+ T cells. This is required for B cells to form germinal centres and to produce high-affinity antibodies.
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The formation of an immunological synapse is associated with a rapid actin-dependent membrane spreading response at the antigen contact site, which increases the amount of BCR–antigen encounters and is required for the formation of signalling microclusters that contain recruited antigens and signalling molecules. This is followed by a contraction phase that is mediated by both the actin and microtubule cytoskeleton, in which antigen-containing microclusters are concentrated at the centre of the synapse by the microtubule motor dynein.
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B cells rapidly relocalize their microtubule-organizing centre (MTOC), together with their MHC class II-containing lysosomes, at the site of antigen encounter — a process that relies on conserved polarity proteins, including the small GTPase cell division control protein 42 (CDC42) and its effector protein atypical protein kinase C type-ζ (PKCζ). Polarized lysosomes are locally secreted, which facilitates synapse acidification and the extracellular release of hydrolases that promote extraction of the immobilized antigens.
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Impairment of MTOC and lysosome polarization via CDC42 or PKCζ silencing compromises antigen processing and presentation to T cells. This highlights how MTOC-dependent exocytosis of secretory lysosomes at the immunological synapse couples antigen extraction to its processing and is crucial for B cells to acquire their antigen presentation function.
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B cells can represent interesting models to study cell polarity, as they acquire polarized phenotypes during different stages of their activation or when scanning for antigens. They acquire these phenotypes through the formation of immunological synapses or as they asymmetrically divide after antigen uptake. Therefore, proteins that regulate B cell polarity are valuable candidates to modulate B cell responses in vivo.
Abstract
B cells are key components of the adaptive immune response. Their differentiation into either specific memory B cells or antibody-secreting plasma cells is a consequence of activation steps that involve the processing and presentation of antigens. The engagement of B cell receptors by surface-tethered antigens leads to the formation of an immunological synapse that coordinates cell signalling events and that promotes antigen uptake for presentation on MHC class II molecules. In this Review, we discuss membrane trafficking and the associated molecular mechanisms that are involved in antigen extraction and processing at the B cell synapse, and we highlight how B cells use cell polarity to coordinate the complex events that ultimately lead to efficient humoral responses.
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References
Mitchison, N. A. T-cell–B-cell cooperation. Nature Rev. Immunol. 4, 308–312 (2004).
Batista, F. D., Iber, D. & Neuberger, M. S. B cells acquire antigen from target cells after synapse formation. Nature 411, 489–494 (2001).
Bertrand, F. E. et al. Microenvironmental influences on human B-cell development. Immunol. Rev. 175, 175–186 (2000).
von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003).
Cyster, J. G. B cell follicles and antigen encounters of the third kind. Nature Immunol. 11, 989–996 (2010).
Carrasco, Y. R. & Batista, F. D. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27, 160–171 (2007).
Junt, T. et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450, 110–114 (2007). References 6 and 7 highlight roles for subcapsular macrophages in the lymph nodes in the presentation of large antigens to B cells in vivo.
Suzuki, K., Grigorova, I., Phan, T. G., Kelly, L. M. & Cyster, J. G. Visualizing B cell capture of cognate antigen from follicular dendritic cells. J. Exp. Med. 206, 1485–1493 (2009).
Qi, H., Egen, J. G., Huang, A. Y. & Germain, R. N. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312, 1672–1676 (2006). References 8 and 9use two-photon microscopy to visualize in vivo how B cells capture antigen from FDCs in primary follicles or from DCs upon entry to the lymph nodes.
Pape, K. A., Catron, D. M., Itano, A. A. & Jenkins, M. K. The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26, 491–502 (2007).
Clark, S. L. Jr. The reticulum of lymph nodes in mice studied with the electron microscope. Am. J. Anat. 110, 217–257 (1962).
Gretz, J. E., Norbury, C. C., Anderson, A. O., Proudfoot, A. E. & Shaw, S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J. Exp. Med. 192, 1425–1440 (2000).
Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nature Rev. Immunol. 9, 15–27 (2009).
Saez de Guinoa, J., Barrio, L., Mellado, M. & Carrasco, Y. R. CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics. Blood 118, 1560–1569 (2011).
Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).
Yuseff, M. I., Lankar, D. & Lennon-Dumenil, A. M. Dynamics of membrane trafficking downstream of B and T cell receptor engagement: impact on immune synapses. Traffic 10, 629–636 (2009).
Carrasco, Y. R., Fleire, S. J., Cameron, T., Dustin, M. L. & Batista, F. D. LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation. Immunity 20, 589–599 (2004).
Cambier, J. C., Pleiman, C. M. & Clark, M. R. Signal transduction by the B cell antigen receptor and its coreceptors. Annu. Rev. Immunol. 12, 457–486 (1994).
Reth, M. & Wienands, J. Initiation and processing of signals from the B cell antigen receptor. Annu. Rev. Immunol. 15, 453–479 (1997).
Baba, Y. & Kurosaki, T. Impact of Ca2+ signaling on B cell function. Trends Immunol. 32, 589–594 (2011).
Fleire, S. J. et al. B cell ligand discrimination through a spreading and contraction response. Science 312, 738–741 (2006). This paper describes the two-phase spreading and contraction response exerted by B cells that are in contact with membrane-bound antigens. This response promotes antigen gathering into a central cluster at the synapse.
Harwood, N. E. & Batista, F. D. Early events in B cell activation. Annu. Rev. Immunol. 28, 185–210 (2010).
Depoil, D. et al. CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nature Immunol. 9, 63–72 (2008).
Depoil, D. et al. Early events of B cell activation by antigen. Sci. Signal. 2, Pt1 (2009).
Tolar, P., Sohn, H. W. & Pierce, S. K. Viewing the antigen-induced initiation of B-cell activation in living cells. Immunol. Rev. 221, 64–76 (2008). This review highlights experiments using live-cell imaging technologies that can be used to show the early spatiotemporal signalling events that occur downstream of BCR engagement.
Treanor, B., Depoil, D., Bruckbauer, A. & Batista, F. D. Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity. J. Exp. Med. 208, 1055–1068 (2011).
Schnyder, T. et al. B cell receptor-mediated antigen gathering requires ubiquitin ligase Cbl and adaptors Grb2 and Dok-3 to recruit dynein to the signaling microcluster. Immunity 34, 905–918 (2011).
Arana, E. et al. Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28, 88–99 (2008).
Lin, K. B. et al. The rap GTPases regulate B cell morphology, immune-synapse formation, and signaling by particulate B cell receptor ligands. Immunity 28, 75–87 (2008).
Freeman, S. A. et al. Cofilin-mediated F-actin severing is regulated by the Rap GTPase and controls the cytoskeletal dynamics that drive lymphocyte spreading and BCR microcluster formation. J. Immunol. 187, 5887–5900 (2011).
Hao, S. & August, A. Actin depolymerization transduces the strength of B-cell receptor stimulation. Mol. Biol. Cell 16, 2275–2284 (2005).
Treanor, B. et al. The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity 32, 187–199 (2010).
Meyer-Bahlburg, A. et al. Wiskott–Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis. Blood 112, 4158–4169 (2008).
Tsourkas, P. K., Baumgarth, N., Simon, S. I. & Raychaudhuri, S. Mechanisms of B-cell synapse formation predicted by Monte Carlo simulation. Biophys. J. 92, 4196–4208 (2007).
Tsourkas, P. K., Longo, M. L. & Raychaudhuri, S. Monte Carlo study of single molecule diffusion can elucidate the mechanism of B cell synapse formation. Biophys. J. 95, 1118–1125 (2008).
Tsourkas, P. K. & Raychaudhuri, S. Modeling of B cell synapse formation by Monte Carlo simulation shows that directed transport of receptor molecules is a potential formation mechanism. Cell. Mol. Bioeng. 3, 256–268 (2010).
Stinchcombe, J. C. et al. Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems. BMC Biol. 9, 45 (2011).
Yuseff, M. I. et al. Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. Immunity 35, 361–374 (2011). This paper was the first to show how B cells use conserved polarity mechanisms to locally recruit and secrete lysosomes at the immunological synapsein order to extract and present immobilized antigens on MHC class II molecules.
Combs, J. et al. Recruitment of dynein to the Jurkat immunological synapse. Proc. Natl Acad. Sci. USA 103, 14883–14888 (2006).
Gomes, E. R., Jani, S. & Gundersen, G. G. Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell 121, 451–463 (2005).
Iden, S. & Collard, J. G. Crosstalk between small GTPases and polarity proteins in cell polarization. Nature Rev. Mol. Cell Biol. 9, 846–859 (2008).
Stinchcombe, J. C., Bossi, G., Booth, S. & Griffiths, G. M. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001).
Poo, W. J., Conrad, L. & Janeway, C. A. Jr. Receptor-directed focusing of lymphokine release by helper T cells. Nature 332, 378–380 (1988).
Stinchcombe, J. C., Majorovits, E., Bossi, G., Fuller, S. & Griffiths, G. M. Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443, 462–465 (2006).
Chemin, K. et al. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J. Immunol. 189, 2159–2168 (2012).
Xu, J. et al. Mechanism of polarized lysosome exocytosis in epithelial cells. J. Cell Sci. 125, 5937–5943 (2012).
Jordens, I., Marsman, M., Kuijl, C. & Neefjes, J. Rab proteins, connecting transport and vesicle fusion. Traffic 6, 1070–1077 (2005).
Weber, T. et al. SNAREpins: minimal machinery for membrane fusion. Cell 92, 759–772 (1998).
Das, V. et al. Activation-induced polarized recycling targets T cell antigen receptors to the immunological synapse; involvement of SNARE complexes. Immunity 20, 577–588 (2004).
Andrews, N. W. Regulated secretion of conventional lysosomes. Trends Cell Biol. 10, 316–321 (2000).
Stinchcombe, J. C. et al. Rab27a is required for regulated secretion in cytotoxic T lymphocytes. J. Cell Biol. 152, 825–834 (2001).
Holt, O. et al. Slp1 and Slp2-a localize to the plasma membrane of CTL and contribute to secretion from the immunological synapse. Traffic 9, 446–457 (2008).
Haka, A. S. et al. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins. Mol. Biol. Cell 20, 4932–4940 (2009).
Aucher, A., Magdeleine, E., Joly, E. & Hudrisier, D. Capture of plasma membrane fragments from target cells by trogocytosis requires signaling in T cells but not in B cells. Blood 111, 5621–5628 (2008).
Joly, E. & Hudrisier, D. What is trogocytosis and what is its purpose? Nature Immunol. 4, 815 (2003).
Arndt, S. O. et al. Functional HLA-DM on the surface of B cells and immature dendritic cells. EMBO J. 19, 1241–1251 (2000).
Santambrogio, L. et al. Extracellular antigen processing and presentation by immature dendritic cells. Proc. Natl Acad. Sci. USA 96, 15056–15061 (1999).
Delamarre, L., Pack, M., Chang, H., Mellman, I. & Trombetta, E. S. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307, 1630–1634 (2005).
Lennon-Dumenil, A. M. et al. Analysis of protease activity in live antigen-presenting cells shows regulation of the phagosomal proteolytic contents during dendritic cell activation. J. Exp. Med. 196, 529–540 (2002).
Lankar, D. et al. Dynamics of major histocompatibility complex class II compartments during B cell receptor-mediated cell activation. J. Exp. Med. 195, 461–472 (2002).
Stoddart, A. et al. Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization. Immunity 17, 451–462 (2002).
Zhang, M. et al. Ubiquitinylation of Igβ dictates the endocytic fate of the B cell antigen receptor. J. Immunol. 179, 4435–4443 (2007).
Drake, L., McGovern-Brindisi, E. M. & Drake, J. R. BCR ubiquitination controls BCR-mediated antigen processing and presentation. Blood 108, 4086–4093 (2006).
Katkere, B., Rosa, S. & Drake, J. R. The Syk-binding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation. J. Biol. Chem. 287, 16636–16644 (2012).
Kim, Y. M. et al. Monovalent ligation of the B cell receptor induces receptor activation but fails to promote antigen presentation. Proc. Natl Acad. Sci. USA 103, 3327–3332 (2006).
Chaturvedi, A., Martz, R., Dorward, D., Waisberg, M. & Pierce, S. K. Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments. Nature Immunol. 12, 1119–1126 (2011).
Chatterjee, P., Tiwari, R. K., Rath, S., Bal, V. & George, A. Modulation of antigen presentation and B cell receptor signaling in B cells of beige mice. J. Immunol. 188, 2695–2702 (2012). This paper shows that BCR signalling that is initiated at the plasma membrane continues in intracellular compartments, initiating a sequential phosphorylation of kinases.
Onabajo, O. O. et al. Actin-binding protein 1 regulates B cell receptor-mediated antigen processing and presentation in response to B cell receptor activation. J. Immunol. 180, 6685–6695 (2008).
Sharma, S., Orlowski, G. & Song, W. Btk regulates B cell receptor-mediated antigen processing and presentation by controlling actin cytoskeleton dynamics in B cells. J. Immunol. 182, 329–339 (2009).
Le Roux, D. et al. Syk-dependent actin dynamics regulate endocytic trafficking and processing of antigens internalized through the B-cell receptor. Mol. Biol. Cell 18, 3451–3462 (2007).
Wang, Q. et al. Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin. J. Cell Biol. 160, 565–575 (2003).
Hornstein, I., Alcover, A. & Katzav, S. Vav proteins, masters of the world of cytoskeleton organization. Cell. Signal. 16, 1–11 (2004).
Weber, M. et al. Phospholipase C-γ2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen. J. Exp. Med. 205, 853–868 (2008).
Gondre-Lewis, T. A., Moquin, A. E. & Drake, J. R. Prolonged antigen persistence within nonterminal late endocytic compartments of antigen-specific B lymphocytes. J. Immunol. 166, 6657–6664 (2001).
Vascotto, F. et al. The actin-based motor protein myosin II regulates MHC class II trafficking and BCR-driven antigen presentation. J. Cell Biol. 176, 1007–1019 (2007).
Pereira, J. P., Kelly, L. M. & Cyster, J. G. Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int. Immunol. 22, 413–419 (2010).
Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002).
Pereira, J. P., Kelly, L. M., Xu, Y. & Cyster, J. G. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009).
Duchez, S., Rodrigues, M., Bertrand, F. & Valitutti, S. Reciprocal polarization of T and B cells at the immunological synapse. J. Immunol. 187, 4571–4580 (2011).
Cunningham, A. F. et al. Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. J. Immunol. 178, 6200–6207 (2007).
Allen, C. D., Okada, T. & Cyster, J. G. Germinal-center organization and cellular dynamics. Immunity 27, 190–202 (2007).
MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).
Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).
Drubin, D. G. & Nelson, W. J. Origins of cell polarity. Cell 84, 335–344 (1996).
Guo, F., Velu, C. S., Grimes, H. L. & Zheng, Y. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood 114, 2909–2916 (2009).
Martin, P. et al. Role of ζ-PKC in B-cell signaling and function. EMBO J. 21, 4049–4057 (2002).
Thaunat, O. et al. Asymmetric segregation of polarized antigen on B cell division shapes presentation capacity. Science 335, 475–479 (2012).
Shlomchik, M. J. & Weisel, F. Germinal center selection and the development of memory B and plasma cells. Immunol. Rev. 247, 52–63 (2012).
Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).
Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010).
Randall, K. L. et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature Immunol. 10, 1283–1291 (2009). This work shows that DOCK8 mutations impair the accumulation of the integrin ligand ICAM1 in the B cell immunological synapse. This leads to B cell-deficient signalling and highlights how humoral immunodeficiency is dependent on the organization of the B cell immunological synapse.
Harada, Y. et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood 119, 4451–4461 (2012).
Hauser, A. E. et al. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26, 655–667 (2007). Using multiphoton in vivo microscopy, this work describes the migration patterns of B cells between the dark and light zones of the germinal centre, detailing the morphological changes that B cells undergo during this movement.
Barnett, B. E. et al. Asymmetric B cell division in the germinal center reaction. Science 335, 342–344 (2012). This study describes how, following cell division, germinal centre B cells asymmetrically segregate molecules that are involved in B cell fate, as well as the ancestral polarity protein PKCζ,to generate unequal daughter cells.
Li, R. & Bowerman, B. Symmetry breaking in biology. Cold Spring Harb. Perspect. Biol. 2, a003475 (2010).
Mogilner, A., Allard, J. & Wollman, R. Cell polarity: quantitative modeling as a tool in cell biology. Science 336, 175–179 (2012).
Hat, B., Kazmierczak, B. & Lipniacki, T. B cell activation triggered by the formation of the small receptor cluster: a computational study. PLoS Comput. Biol. 7, e1002197 (2011).
Tsourkas, P. K., Liu, W., Das, S. C., Pierce, S. K. & Raychaudhuri, S. Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement. Cell. Mol. Immunol. 9, 62–74 (2011).
Goehring, N. W. et al. Polarization of PAR proteins by advective triggering of a pattern-forming system. Science 334, 1137–1141 (2011).
Wan, Z. et al. B cell activation is regulated by the stiffness properties of the substrate presenting the antigens. J. Immunol. 190, 4661–4675 (2013).
Wedlich-Soldner, R., Altschuler, S., Wu, L. & Li, R. Spontaneous cell polarization through actomyosin-based delivery of the Cdc42 GTPase. Science 299, 1231–1235 (2003). This is an important paper, showing the role of CDC42 in cell polarity. In this paper, experiments that are corroborated by a mathematical model show that a stable axis of polarity arises in yeast from a positive feedback mechanism that amplifies a random concentration of activated CDC42. This work suggests that spontaneous polarization might occur and could be stabilized by external cues.
Gierer, A. & Meinhardt, H. A theory of biological pattern formation. Kybernetik 12, 30–39 (1972).
Jilkine, A. & Edelstein-Keshet, L. A comparison of mathematical models for polarization of single eukaryotic cells in response to guided cues. PLoS Comput. Biol. 7, e1001121 (2011). This paper is a detailed survey of the different models of cell polarity. The authors identify the general features of a polarizing cell that are common to all systems, they highlight the advantages and the disadvantages of different mathematical models and they test the response of the different models to a given stimulus.
Baracho, G. V., Miletic, A. V., Omori, S. A., Cato, M. H. & Rickert, R. C. Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation. Curr. Opin. Immunol. 23, 178–183 (2011).
Liu, C. et al. A balance of Bruton's tyrosine kinase and SHIP activation regulates B cell receptor cluster formation by controlling actin remodeling. J. Immunol. 187, 230–239 (2011).
Houk, A. R. et al. Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration. Cell 148, 175–188 (2012).
Wedlich-Soldner, R. & Li, R. Spontaneous cell polarization: undermining determinism. Nature Cell Biol. 5, 267–270 (2003).
Mattila, P. K. et al. The actin and tetraspanin networks organize receptor nanoclusters to regulate B cell receptor-mediated signaling. Immunity 38, 461–474 (2013).
Cheng, P. C., Steele, C. R., Gu, L., Song, W. & Pierce, S. K. MHC class II antigen processing in B cells: accelerated intracellular targeting of antigens. J. Immunol. 162, 7171–7180 (1999).
Forquet, F. et al. Presentation of antigens internalized through the B cell receptor requires newly synthesized MHC class II molecules. J. Immunol. 162, 3408–3416 (1999).
Wolf, P. R. & Ploegh, H. L. How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. Annu. Rev. Cell Dev. Biol. 11, 267–306 (1995).
Villadangos, J. A. et al. Proteases involved in MHC class II antigen presentation. Immunol. Rev. 172, 109–120 (1999).
Watts, C. Antigen processing in the endocytic compartment. Curr. Opin. Immunol. 13, 26–31 (2001).
Brezski, R. J. & Monroe, J. G. B cell antigen receptor-induced Rac1 activation and Rac1-dependent spreading are impaired in transitional immature B cells due to levels of membrane cholesterol. J. Immunol. 179, 4464–4472 (2007).
Walmsley, M. J. et al. Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 302, 459–462 (2003).
Westerberg, L. S. et al. Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function. Blood 119, 3966–3974 (2012).
Acknowledgements
The authors kindly thank C. Hivroz, Y. R. Carrasco, D. Obino and D. Lankar for discussions and critical reading of the manuscript. This work was funded by grants from the European Research Council to A.-M.L.-D. and the L'Agence nationale de la recherche Jeunes Chercheuses et Jeunes Chercheurs programme to P.P.
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FURTHER INFORMATION
Glossary
- Immunological synapse
-
The interface between an antigen-presenting cell and a lymphocyte. The hallmark of this structure comprises two concentric regions: one region that is referred to as the central supramolecular activation cluster (cSMAC), where immune receptors are enriched, and another region that is referred to as the peripheral SMAC (pSMAC), which contains adhesion molecules such as lymphocyte function-associated 1 (LFA1) bound to its ligand intercellular adhesion molecule 1 (ICAM1).
- Cell polarity
-
The asymmetric organization of both functional and structural cell components, which are crucial to coordinate diverse biological functions ranging from directional cell migration and asymmetric cell division to the maintenance of tissue integrity.
- CXC-chemokine ligand 13
-
(CXCL13). A chemokine belonging to the CXC-chemokine family that functions as a chemoattractant for B cells by binding to CXC-chemokine receptor 5 (CXCR5).
- Lymphocyte function-associated antigen 1
-
(LFA1). An integrin that is formed by the α-integrin (also known as CD11a) and β-integrin (also known as CD18) chains, It is present in diverse cell types of the immune system, such as lymphocytes, macrophages and neutrophils. LFA1 binds to its ligand intercellular adhesion molecule 1 (ICAM1), which is present on the cell surface of antigen-presenting cells. In B cells, it promotes cell adhesion and antigen gathering during immunological synapse formation, thereby facilitating B cell activation.
- Kinapses
-
Motile adhesive interactions between lymphocytes and antigen-presenting cells. They differ from synapses because the interactions can be transitory.
- ERM proteins
-
A family of three closely related proteins formed by ezrin, radixin and moesin that connect actin filaments with the plasma membrane. They possess a FERM (protein 4.1, ezrin, radixin and moesin) domain that mediates interactions with proteins in the plasma membrane and a charged carboxyl terminus that interacts with actin filaments.
- Stochastic simulations
-
A system of particles can be described by its equations of motion. In a system that is subject to thermal fluctuations it is necessary to include a stochastic (random) term that accounts for these fluctuations. By using stochastic simulations a numerical integration of these equations can be generated. Quantities that are experimentally measurable are obtained by averaging several realizations of the process.
- Microtubule organizing centre
-
(MTOC; also known as the centrosome in animal cells). A major site of microtubule nucleation that is enriched in α-tubulin. This dynamic structure organizes the mitotic and meiotic spindle and basal bodies that are associated with cilia.
- Lysosomes
-
The central degradative compartments of the cell. The lysosomes contain an acidic pH (4.6–5.0) and they are where lysosomal hydrolases are concentrated.
- Atypical protein kinase C ζ-type
-
(PKCζ). An atypical member of the PKC family that does not require either calcium or diacylglycerol for its activation. It associates with partitioning defective 3 (PAR3) to regulate cell polarity in diverse cell types.
- Cell division control protein 42
-
(CDC42). A RHO-GTPase that controls diverse cellular functions including cell morphology, migration and cell division. By interacting with Wiskott–Aldrich syndrome protein (WASP), CDC42 regulates actin polymerization.
- Asymmetric cell division
-
A cell division in which the organelles and proteins do not distribute equally, giving rise to two daughter cells with different properties and fates. This is required for cell specialization and mainly relies on asymmetry in the spindle position during the prophase stage of mitosis. Notably, stem cells can divide asymmetrically to give rise to two distinct daughter cells: one cell that is a copy of themselves and one cell that is programmed to differentiate into another cell type.
- Total internal reflection fluorescence microscopy
-
(TIRFM). A fluorescence microscopy technique that involves illuminating and observing a thin layer of the specimen (about 200 nm) close to the cover slip using an 'evanescent wave' (which is formed when a laser encounters the glass surface above the critical angle in such a way that it is 'totally reflected'). It combines the speed and the resolution of the usual fluorescence microscopy (being an example of widefield microscopy) with the possibility of excluding excitation and emission from unwanted planes, providing a high signal to noise ratio.
- Beige mice
-
Members of a mouse strain typified by beige hair that carry the lysosomal trafficking regulator (Lyst) mutation.These mice have an autosomal recessive disorder that is characterized by hypopigmentation and immune cell dysfunction. Beige mouse abnormalities result from aberrant lysosomal trafficking and are similar to those of patients with Chediak–Higashi syndrome.
- Uropod
-
Protrusion of the plasma membrane that forms at the rear end of migrating cells.
- Filopodia
-
Dynamic actin-rich filamentous protrusions that extend from cells.
- Symmetry breaking
-
The process by which a system switches from a disordered or a uniform state to a state in which an ordered shape, direction or pattern is established; for example, proteins that are normally uniformly distributed will concentrate at a single spot after receiving a certain stimulus.
- Mechanosensing
-
The capacity of cells to sense mechanical stimuli, such as deformation of the membrane, the cortex, the nucleus and other structures, or to sense changes in the adhesive properties of the substrate.
- Membrane tension
-
A measure of how stretched the cell membrane is to compensate for the osmotic pressure of the cytoplasm. It can be modified by changing the osmotic pressure of the medium and can be measured by micromanipulation techniques measuring the force necessary to pull tubes of membrane.
- Partitioning defective 3
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(PAR3). Together with PAR6 these proteins form the PAR polarity complex and are both scaffolding proteins that are implicated in cell polarity. PAR3 and PAR6 bind to each other via their PDZ (PSD95, DLGA and ZO1 homology) domains. They localize at the plasma membrane via atypical protein kinase C ζ-type, cell division control protein 42 (bound to PAR6) or via their PDZ domains.
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Yuseff, MI., Pierobon, P., Reversat, A. et al. How B cells capture, process and present antigens: a crucial role for cell polarity. Nat Rev Immunol 13, 475–486 (2013). https://doi.org/10.1038/nri3469
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DOI: https://doi.org/10.1038/nri3469
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