Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The tipping points in the initiation of B cell signalling: how small changes make big differences

Nature Reviews Immunology volume 10, pages 767–777 (2010)Cite this article

Subjects

Key Points

  • B cells are activated by the binding of antigen to the cell surface-expressed B cell receptor (BCR), which triggers a number of signalling cascades. Although we understand the biochemical nature of these cascades in considerable detail, with the application of several new high-resolution imaging technologies we are just learning about the earliest events that follow antigen binding to the BCR.

  • B cells recognize antigen both in solution and on the surface of antigen-presenting cells (APCs), and although in both cases the BCRs cluster and initiate signalling, the molecular mechanisms that underlie clustering and signal transduction do not seem to be identical in the two cases.

  • BCR clustering in response to antigens in solution requires physical crosslinking of the BCRs by multivalent antigens. By contrast, BCRs form microclusters in response to monovalent antigen when this is presented on an APC in the absence of physical crosslinking of the BCR.

  • For BCR oligomerization and clustering in response to monovalent antigen on APCs, the Cμ4 portion of the ectodomain of the membrane-bound immunoglobulin of the BCR is both necessary and sufficient. Current data fit a model for the initiation of BCR signalling termed 'the conformation-induced oligomerization model'.

  • The early events in BCR oligomerization and clustering are BCR intrinsic and do not depend on activation of the signalling cascades. These BCR-intrinsic events are sensitive to antigen affinity and the isotype of the BCR, and are regulated by B cell co-receptors.

  • The information that the BCR has bound antigen may be transduced across the membrane to the cytoplasm to initiate signalling by perturbations in either the local lipid environment of the BCR or the orientation of the chains that compose the BCR.

Abstract

B cells are selected by the binding of antigen to clonally distributed B cell receptors (BCRs), triggering signalling cascades that result in B cell activation. With the recent application of high-resolution live-cell imaging, we are gaining an understanding of the events that initiate BCR signalling within seconds of its engagement with antigen. These observations are providing a molecular explanation for fundamental aspects of B cell responses, including antigen affinity discrimination and the value of class switching, as well as insights into the underlying causes of B cell tumorigenesis. Advances in our understanding of the earliest molecular events that follow antigen binding to the BCR may provide a general framework for the initiation of signalling in the adaptive immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The structural organization of the B cell receptor.
Figure 2: The 'conformation-induced oligomerization model' for B cell receptor microcluster formation.
Figure 3: B cell microclusters grow with time after antigen binding.
Figure 4: Models for how B cell receptor oligomers trigger signalling.

Similar content being viewed by others

References

  1. McHeyzer-Williams, L. J. & McHeyzer-Williams, M. G. Antigen-specific memory B cell development. Annu. Rev. Immunol. 23, 487–513 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Tarlinton, D. B-cell memory: are subsets necessary? Nature Rev. Immunol. 6, 785–790 (2006).

    Article  CAS  Google Scholar 

  3. Rajewsky, K. Clonal selection and learning in the antibody system. Nature 381, 751–758 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Reth, M. & Wienands, J. Initiation and processing of signals from the B cell antigen receptor. Annu. Rev. Immunol. 15, 453–479 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Tolar, P., Sohn, H. W. & Pierce, S. K. The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer. Nature Immunol. 6, 1168–1176 (2005).

    Article  CAS  Google Scholar 

  6. DeFranco, A. L. The complexity of signaling pathways activated by the BCR. Curr. Opin. Immunol. 9, 296–308 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Dal Porto, J. M. et al. B cell antigen receptor signaling 101. Mol. Immunol. 41, 599–613 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009). Using an elegant genetic approach, these authors demonstrated that BCR-deficient mature B cells can be rescued by PI3K signalling, suggesting the molecular nature of the survival signal delivered by BCRs in mature B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Grande, S. M., Bannish, G., Fuentes-Panana, E. M., Katz, E. & Monroe, J. G. Tonic B-cell and viral ITAM signaling: context is everything. Immunol. Rev. 218, 214–234 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Delgado, P. et al. Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nature Immunol. 10, 880–888 (2009).

    Article  CAS  Google Scholar 

  11. Tolar, P., Hanna, J., Krueger, P. D. & Pierce, S. K. The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens. Immunity 30, 44–55 (2009). In this study, two-colour TIRFM SPT was used to demonstrate that monovalent membrane-associated antigen induced the formation of immobile BCR oligomers, a very early event in the initiation of BCR signalling, and that the oligomerization depended on the constant region of the BCR's membrane immunoglobulin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Treanor, B. et al. The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity 32, 187–199 (2010). This study used two-colour TIRFM SPT to image BCRs and the membrane cytoskeleton, and provided evidence for the restriction of BCR mobility by the membrane cytoskeleton. The authors also showed that simply disrupting the membrane cytoskeleton network in resting B cells induced BCR signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, J. & Reth, M. Oligomeric organization of the B-cell antigen receptor on resting cells. Nature 5 Sep 2010 (doi:10.1038/nature09357).

    Article  CAS  PubMed  Google Scholar 

  14. Gauthier, L., Rossi, B., Roux, F., Termine, E. & Schiff, C. Galectin-1 is a stromal cell ligand of the pre-B cell receptor (BCR) implicated in synapse formation between pre-B and stromal cells and in pre-BCR triggering. Proc. Natl Acad. Sci. USA 99, 13014–13019 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. Phan, T. G., Grigorova, I., Okada, T. & Cyster, J. G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nature Immunol. 8, 992–1000 (2007).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Schwickert, T. A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Batista, F. D., Iber, D. & Neuberger, M. S. B cells acquire antigen from target cells after synapse formation. Nature 411, 489–494 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Fleire, S. J. et al. B cell ligand discrimination through a spreading and contraction response. Science 312, 738–741 (2006). Scanning electron microscopy (SEM) and confocal laser-scanning microscopy (CLSM) were used to describe the spreading and contraction responses of B cells encountering membrane-bound antigens, leading to B cell activation.

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Lin, K. B. L. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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). References 23–25 report the identification of the molecular requirements for the B cell spreading and contraction response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Metzger, H. Transmembrane signaling: the joy of aggregation. J. Immunol. 149, 1477–1487 (1992).

    CAS  PubMed  Google Scholar 

  27. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Hubbard, S. R. & Miller, W. T. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr. Opin. Cell Biol. 19, 117–123 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ihle, J. N. & Kerr, I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 11, 69–74 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541–552 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Kusumi, A. et al. Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu. Rev. Biophys. Biomol. Struct. 34, 351–378 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Kusumi, A., Shirai, Y. M., Koyama-Honda, I., Suzuki, K. G. & Fujiwara, T. K. Hierarchical organization of the plasma membrane: investigations by single-molecule tracking vs. fluorescence correlation spectroscopy. FEBS Lett. 584, 1814–1823 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Tolar, P. & Pierce, S. K. A conformation-induced oligomerization model for B cell receptor microclustering and signaling. Curr. Top. Microbiol. Immunol. 340, 155–169 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, W., Meckel, T., Tolar, P., Sohn, H. W. & Pierce, S. K. Antigen affinity discrimination is an intrinsic function of the B cell receptor. J. Exp. Med. 207, 1095–1111 (2010). In this study, the early BCR-intrinsic molecular events in the initiation of BCR signalling were determined to be sensitive to the affinity of the BCR for antigen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gray, D. Immunological memory. Annu. Rev. Immunol. 11, 49–77 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Brink, R., Phan, T. G., Paus, D. & Chan, T. D. Visualizing the effects of antigen affinity on T-dependent B-cell differentiation. Immunol. Cell Biol. 86, 31–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Dal Porto, J. M., Haberman, A. M., Kelsoe, G. & Shlomchik, M. J. Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J. Exp. Med. 195, 1215–1221 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shih, T. A., Meffre, E., Roederer, M. & Nussenzweig, M. C. Role of BCR affinity in T cell dependent antibody responses in vivo. Nature Immunol. 3, 570–575 (2002).

    Article  CAS  Google Scholar 

  39. Shih, T. A., Roederer, M. & Nussenzweig, M. C. Role of antigen receptor affinity in T cell-independent antibody responses in vivo. Nature Immunol. 3, 399–406 (2002).

    Article  CAS  Google Scholar 

  40. Takahashi, Y., Dutta, P. R., Cerasoli, D. M. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection. J. Exp. Med. 187, 885–895 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Paus, D. et al. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J. Exp. Med. 203, 1081–1091 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Phan, T. G. et al. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203, 2419–2424 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kouskoff, V. et al. Antigens varying in affinity for the B cell receptor induce differential B lymphocyte responses. J. Exp. Med. 188, 1453–1464 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kaisho, T., Schwenk, F. & Rajewsky, K. The roles of γ1 heavy chain membrane expression and cytoplasmic tail in IgG1 responses. Science 276, 412–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Martin, S. W. & Goodnow, C. C. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nature Immunol. 3, 182–188 (2002). In references 44 and 45, the highly conserved cytoplasmic tail of membrane-bound IgG was demonstrated to be both necessary and sufficient for enhanced IgG memory antibody responses in vivo.

    Article  CAS  Google Scholar 

  46. Horikawa, K. et al. Enhancement and suppression of signaling by the conserved tail of IgG memory-type B cell antigen receptors. J. Exp. Med. 204, 759–769 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Waisman, A. et al. IgG1 B cell receptor signaling is inhibited by CD22 and promotes the development of B cells whose survival is less dependent on Igα/β. J. Exp. Med. 204, 747–758 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wakabayashi, C., Adachi, T., Wienands, J. & Tsubata, T. A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 298, 2392–2395 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Engels, N. et al. Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells. Nature Immunol. 10, 1018–1025 (2009). This study showed that a conserved tyrosine in the cytoplasmic domain of membrane-bound IgG and membrane-bound IgE was phosphorylated upon BCR crosslinking. This recruited the adaptor molecule GRB2 to the BCR, resulting in enhanced calcium response and B cell proliferation.

    Article  CAS  Google Scholar 

  50. Liu, W., Meckel, T., Tolar, P., Sohn, H. W. & Pierce, S. K. Intrinsic properties of immunoglobulin IgG1 isotype-switched B cell receptors promote microclustering and the initiation of signaling. Immunity 32, 778–789 (2010). In this study, the early BCR-intrinsic molecular events in the initiation of BCR signalling were found to be sensitive to the isotype of the BCR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nature Rev. Mol. Cell Biol. 1, 31–39 (2000).

    Article  CAS  Google Scholar 

  52. Dykstra, M., Cherukuri, A., Sohn, H. W., Tzeng, S. J. & Pierce, S. K. Location is everything: lipid rafts and immune cell signaling. Annu. Rev. Immunol. 21, 457–481 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Sohn, H. W., Tolar, P. & Pierce, S. K. Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse. J. Cell Biol. 182, 367–379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Viola, A. & Gupta, N. Tether and trap: regulation of membrane-raft dynamics by actin-binding proteins. Nature Rev. Immunol. 7, 889–896 (2007).

    Article  CAS  Google Scholar 

  55. Sohn, H. W., Tolar, P., Jin, T. & Pierce, S. K. Fluorescence resonance energy transfer in living cells reveals dynamic membrane changes in the initiation of B cell signaling. Proc. Natl Acad. Sci. USA 103, 8143–8148 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McIntosh, T. J., Vidal, A. & Simon, S. A. Sorting of lipids and transmembrane peptides between detergent-soluble bilayers and detergent-resistant rafts. Biophys. J. 85, 1656–1666 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Reynwar, B. J. et al. Aggregation and vesiculation of membrane proteins by curvature-mediated interactions. Nature 447, 461–464 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ɛ cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008). FRET and nuclear magnetic resonance techniques were used to demonstrate that the tyrosine motif within the cytoplasmic domain of the TCR CD3ɛ chain is inserted into the plasma membrane and is not available for phosphorylation until the TCR binds its ligand.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Radaev, S. et al. Structural and functional studies of Igαβ and its assembly with the B cell antigen receptor. Structure 18, 934–943 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nature Rev. Immunol. 8, 34–47 (2008).

    Article  CAS  Google Scholar 

  61. Liu, W., Won Sohn, H., Tolar, P., Meckel, T. & Pierce, S. K. Antigen-induced oligomerization of the B cell receptor is an early target of FcγRIIB inhibition. J. Immunol. 184, 1977–1989 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Floto, R. A. et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nature Med. 11, 1056–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Kono, H. et al. FcγRIIB IIe232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum. Mol. Genet. 14, 2881–2892 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. 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). This study showed the essential function of the BCR co-receptor CD19 in the initiation of BCR signalling in response to membrane-bound antigens.

    Article  CAS  Google Scholar 

  65. Fearon, D. T. & Carroll, M. C. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu. Rev. Immunol. 18, 393–422 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010). This study showed that the BCRs in B cell lymphomas that are dependent on BCRs for their survival spontaneously form prominent immobile clusters in the plasma membrane similar to antigen-stimulated BCRs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Matskova, L., Ernberg, I., Pawson, T. & Winberg, G. C-terminal domain of the Epstein-Barr virus LMP2A membrane protein contains a clustering signal. J. Virol. 75, 10941–10949 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Douglass, A. D. & Vale, R. D. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Cell 121, 937–950 (2005). This study used two-colour SPT in conjunction with CLSM technique to show that antigen engagement of the TCR resulted in immobilization in TCR microclusters of LCK, CD2 and LAT molecules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Balakrishnan, K., Hsu, F. J., Cooper, A. D. & McConnell, H. M. Lipid hapten containing membrane targets can trigger specific immunoglobulin E-dependent degranulation of rat basophil leukemia cells. J. Biol. Chem. 257, 6427–6433 (1982).

    CAS  PubMed  Google Scholar 

  70. Weis, R. M., Balakrishnan, K., Smith, B. A. & McConnell, H. M. Stimulation of fluorescence in a small contact region between rat basophil leukemia cells and planar lipid membrane targets by coherent evanescent radiation. J. Biol. Chem. 257, 6440–6445 (1982).

    CAS  PubMed  Google Scholar 

  71. Andrews, N. L. et al. Actin restricts FcɛRI diffusion and facilitates antigen-induced receptor immobilization. Nature Cell Biol. 10, 955–963 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Andrews, N. L. et al. Small, mobile FcɛRI receptor aggregates are signaling competent. Immunity 31, 469–479 (2009). In references 71 and 72, the authors used a quantum-dot-based SPT technique to image FcɛR1 mobility on ligand binding, and showed that highly mobile FcɛR1 molecules became immobilized within seconds of antigen binding in an actin-dependent manner at high antigen concentration, whereas at low antigen concentration the FcɛR1 aggregates were mobile and signalling active.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bajenoff, M. & Germain, R. N. Seeing is believing: a focus on the contribution of microscopic imaging to our understanding of immune system function. Eur. J. Immunol. 37, S18–S33 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Dehmelt, L. & Bastiaens, P. I. Spatial organization of intracellular communication: insights from imaging. Nature Rev. Mol. Cell Biol. 11, 440–452 (2010).

    Article  CAS  Google Scholar 

  75. Coombes, J. L. & Robey, E. A. Dynamic imaging of host–pathogen interactions in vivo. Nature Rev. Immunol. 10, 353–364 (2010).

    Article  CAS  Google Scholar 

  76. Groves, J. T., Parthasarathy, R. & Forstner, M. B. Fluorescence imaging of membrane dynamics. Annu. Rev. Biomed. Eng. 10, 311–338 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Vogel, S. S., Thaler, C. & Koushik, S. V. Fanciful FRET. Sci. STKE 2006, re2 (2006).

    PubMed  Google Scholar 

  78. Sohn, H. W., Tolar, P., Brzostowski, J. & Pierce, S. K. A method for analyzing protein-protein interactions in the plasma membrane of live B cells by fluorescence resonance energy transfer imaging as acquired by total internal reflection fluorescence microscopy. Methods Mol. Biol. 591, 159–183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vale, R. D. Microscopes for fluorimeters: the era of single molecule measurements. Cell 135, 779–785 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Resch-Genger, U., Grabolle, M., Cavaliere-Jaricot, S., Nitschke, R. & Nann, T. Quantum dots versus organic dyes as fluorescent labels. Nature Methods 5, 763–775 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Singer, S. J. & Nicolson, G. L. The fluid mosaic model of the structure of cell membranes. Science 175, 720–731 (1972).

    Article  CAS  PubMed  Google Scholar 

  82. Fujiwara, T., Ritchie, K., Murakoshi, H., Jacobson, K. & Kusumi, A. Phospholipids undergo hop diffusion in compartmentalized cell membrane. J. Cell Biol. 157, 1071–1081 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Morone, N. et al. Three-dimensional reconstruction of the membrane skeleton at the plasma membrane interface by electron tomography. J. Cell Biol. 174, 851–862 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Brzostowski for expert comments on live-cell imaging techniques. This work has been supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

Author information

Authors and Affiliations

  1. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, 20852, Maryland, USA

    Susan K. Pierce & Wanli Liu

Authors
  1. Susan K. Pierce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wanli Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan K. Pierce.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 figure

Dynamics of monomeric versus oligomeric BCRs. (PDF 192 kb)

Supplementary information S2 figure

Structure of the ectodomains of an Igα–Igβ heterodimer. (PDF 284 kb)

Related links

Related links

FURTHER INFORMATION

Susan K. Pierce's homepage

Glossary

Somatic hypermutation

A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibodies, somatic hypermutation leads to affinity maturation of B cells in germinal centres.

Class switching

The somatic recombination process by which the class of immunoglobulin is switched from IgM to IgG, IgA or IgE.

Microclusters

Microscopic assemblies of receptor oligomers in the plasma membrane that recruit signalling molecules. They first form in the contact areas between the B cell and antigen-presenting cell, and ultimately form the central supramolecular activation cluster of the immune synapse.

BCR clustering and capping

The binding of multivalent ligands to B cell receptors (BCRs) induces the redistribution and aggregation of the bound receptors into clusters (clustering). Capping, which requires metabolic energy and cytoskeleton dynamics, represents the coalescence of clusters to form a single aggregate called a cap.

Immune synapse

The specialized contact area between a T or B cell and one or more antigen-presenting cells. The synapse is dynamic and shows lipid and protein segregation, signalling compartmentalization and bidirectional information exchange through soluble and membrane-bound transmitters.

Lamellipodia

Thin sheet-like processes that extend at the leading edge of moving cells. They are actin-rich zones formed in response to chemokine signals, and propel a migrating cell forward.

Lipid rafts

Cholesterol- and sphingolipid-rich membrane microdomains that provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes.

Small interfering RNA

Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference, a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pierce, S., Liu, W. The tipping points in the initiation of B cell signalling: how small changes make big differences. Nat Rev Immunol 10, 767–777 (2010). https://doi.org/10.1038/nri2853

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2853

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing