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A Conformation-Induced Oligomerization Model for B cell Receptor Microclustering and Signaling

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Immunological Synapse

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 340))

Abstract

The B cell receptor (BCR) generates both antigen-independent and dependent intracellular signals that are essential for B cell development and antibody responses against pathogens. However, the molecular mechanisms underlying the initiation of BCR signaling are not understood completely yet. The advent of new imaging technologies is allowing the earliest events in B cell signaling to be viewed both in vivo in lymphoid tissues and in vitro in living cells, in real-time, down to the single molecule level. Here we review recent progress in the use of these technologies to decipher the earliest events that follow B cell antigen recognition. Based on recent data using these techniques, we propose a model for the initiation of BCR signaling in which the binding of antigen induces a conformational change in the BCR’s extracellular domains leading to BCR oligomerization and signaling. We conclude that testing this model will require an in-depth understanding of the unique structural and organizational features of the BCR in the plasma membrane of living B cells in the presence and absence of antigen.

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References

  • Arana E, Vehlow A, Harwood NE, Vigorito E, Henderson R, Turner M, Tybulewicz VL, Batista FD (2008) Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28:88–99

    Article  CAS  PubMed  Google Scholar 

  • Bankovich AJ, Raunser S, Juo ZS, Walz T, Davis MM, Garcia KC (2007) Structural insight into pre-B cell receptor function. Science 316:291–294

    Article  CAS  PubMed  Google Scholar 

  • Batista FD, Neuberger MS (1998) Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity 8:751–759

    Article  CAS  PubMed  Google Scholar 

  • Batista FD, Iber D, Neuberger MS (2001) B cells acquire antigen from target cells after synapse formation. Nature 411:489–494

    Article  CAS  PubMed  Google Scholar 

  • Batten M, Groom J, Cachero TG, Qian F, Schneider P, Tschopp J, Browning JL, Mackay F (2000) BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 192:1453

    Article  CAS  PubMed  Google Scholar 

  • Brezski RJ, Monroe JG (2008) B-cell receptor. Adv Exp Med Biol 640:12–21

    Article  CAS  PubMed  Google Scholar 

  • Campbell KS (1999) Signal transduction from the B cell antigen-receptor. Curr Opin Immunol 11:256–264

    Article  CAS  PubMed  Google Scholar 

  • Carrasco YR, Batista FD (2007) 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

    Article  CAS  PubMed  Google Scholar 

  • Carrasco YR, Fleire SJ, Cameron T, Dustin ML, Batista FD (2004) LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation. Immunity 20:589–599

    Article  CAS  PubMed  Google Scholar 

  • Corcos D, Iglesias A, Dunda O, Bucchini D, Jami J (1991) Allelic exclusion in transgenic mice expressing a heavy chain disease-like human mu protein. Eur J Immunol 21:2711–2716

    Article  CAS  PubMed  Google Scholar 

  • Corcos D, Dunda O, Butor C, Cesbron JY, Lorès P, Bucchini D, Jami J (1995) Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein. Curr Biol 5:1140–1148

    Article  CAS  PubMed  Google Scholar 

  • Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J (2004) B cell antigen receptor signaling 101. Mol Immunol 41:599–613

    Article  CAS  PubMed  Google Scholar 

  • Depoil D, Fleire S, Treanor BL, Weber M, Harwood NE, Marchbank KL, Tybulewicz VL, Batista FD (2008) CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol 9:63–72

    Article  CAS  PubMed  Google Scholar 

  • Fleire SJ, Goldman JP, Carrasco YR, Weber M, Bray D, Batista FD (2006) B cell ligand discrimination through a spreading and contraction response. Science 312:738–741

    Article  CAS  PubMed  Google Scholar 

  • Giannone G, Dubin-Thaler BJ, Rossier O, Cai Y, Chaga O, Jiang G, Beaver W, Dobereiner H-G, Freund Y, Borisy G et al (2007) Lamellipodial actin mechanically links myosin activity with adhesion-site formation. Cell 128:561

    Article  CAS  PubMed  Google Scholar 

  • Herr AB, Ballister ER, Bjorkman PJ (2003) Insights into IgA-mediated immune responses from the crystal structures of human Fc[alpha]RI and its complex with IgA1-Fc. Nature 423:614

    Article  CAS  PubMed  Google Scholar 

  • Huber R, Deisenhofer J, Colman PM, Matsushima M, Palm W (1976) Crystallographic structure studies of an IgG molecule and an Fc fragment. Nature 264:415–420

    Article  CAS  PubMed  Google Scholar 

  • Junt T, Moseman EA, Iannacone M, Massberg S, Lang PA, Boes M, Fink K, Henrickson SE, Shayakhmetov DM, Di Paolo NC et al (2007) Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450:110

    Article  CAS  PubMed  Google Scholar 

  • Kim YM, Pan JY, Korbel GA, Peperzak V, Boes M, Ploegh HL (2006) Monovalent ligation of the B cell receptor induces receptor activation but fails to promote antigen presentation. Proc Natl Acad Sci USA 103:3327–3332

    Article  CAS  PubMed  Google Scholar 

  • Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K (2004) Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell 117:787–800

    Article  CAS  PubMed  Google Scholar 

  • Kurosaki T (1999) Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol 17:555–592

    Article  CAS  PubMed  Google Scholar 

  • Løset GA, Roux KH, Zhu P, Michaelsen TE, Sandlie I (2004) Differential segmental flexibility and reach dictate the antigen binding mode of chimeric IgD and IgM: implications for the function of the B cell receptor. J Immunol 172:2925–2934

    PubMed  Google Scholar 

  • Metzger H (1974) Effect of antigen binding on the properties of antibody. Adv Immunol 18:169–207

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Minguet S, Schamel WW (2008) Permissive geometry model. Adv Exp Med Biol 640:113–120

    Article  CAS  PubMed  Google Scholar 

  • Møller NP (1979) Fc-mediated immune precipitation. I. A new role of the Fc-portion of IgG. Immunology 38:631–640

    PubMed  Google Scholar 

  • Møller NP, Christiansen G (1983) Fc-mediated immune precipitation. III. Visualization by electron microscopy. Immunology 48:469–476

    PubMed  Google Scholar 

  • Monroe JG (2006) ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol 6:283–294

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi K, Melchers F (2003) The nonimmunoglobulin portion of lambda5 mediates cell-autonomous pre-B cell receptor signaling. Nat Immunol 4:849–856

    Article  CAS  PubMed  Google Scholar 

  • Pape KA, Catron DM, Itano AA, Jenkins MK (2007) The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26:491–502

    Article  CAS  PubMed  Google Scholar 

  • Phan TG, Grigorova I, Okada T, Cyster JG (2007) Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat Immunol 8:992–1000

    Article  CAS  PubMed  Google Scholar 

  • Qi H, Egen JG, Huang AY, Germain RN (2006) Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312:1672–1676

    Article  CAS  PubMed  Google Scholar 

  • Radaev S, Motyka S, Fridman WH, Sautes-Fridman C, Sun PD (2001) The structure of a human type III Fcgamma receptor in complex with Fc. J Biol Chem 276:16469–16477

    Article  CAS  PubMed  Google Scholar 

  • Reth M (1992) Antigen receptors on B lymphocytes. Annu Rev Immunol 10:97–121

    Article  CAS  PubMed  Google Scholar 

  • Reth M, Wienands J, Schamel WW (2000) An unsolved problem of the clonal selection theory and the model of an oligomeric B-cell antigen receptor. Immunol Rev 176:10–18

    Article  CAS  PubMed  Google Scholar 

  • Schamel WW, Reth M (2000) Monomeric and oligomeric complexes of the B cell antigen receptor. Immunity 13:5–14

    Article  CAS  PubMed  Google Scholar 

  • Shaffer AL, Rosenwald A, Staudt LM (2002) Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2:920

    Article  CAS  PubMed  Google Scholar 

  • Sigalov A, Aivazian D, Stern L (2004) Homooligomerization of the cytoplasmic domain of the T cell receptor ζ chain and of other proteins containing the immunoreceptor tyrosine-based activation motif. Biochemistry 43:2049–2061

    Article  CAS  PubMed  Google Scholar 

  • Smith A, Sengupta K, Goennenwein S, Seifert U, Sackmann E (2008) Force-induced growth of adhesion domains is controlled by receptor mobility. Proc Natl Acad Sci USA 105:6906

    Article  CAS  PubMed  Google Scholar 

  • Sohn HW, Tolar P, Jin T, Pierce SK (2006) 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

    Article  CAS  PubMed  Google Scholar 

  • Sohn HW, Pierce SK, Tzeng SJ (2008a) Live cell imaging reveals that the inhibitory FcgammaRIIB destabilizes B cell receptor membrane-lipid interactions and blocks immune synapse formation. J Immunol 180:793–799

    CAS  PubMed  Google Scholar 

  • Sohn HW, Tolar P, Pierce SK (2008b) Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse. J Cell Biol 182:367–379

    Article  CAS  PubMed  Google Scholar 

  • Stadanlick JE, Kaileh M, Karnell FG, Scholz JL, Miller JP, Iii WJQ, Brezski RJ, Treml LS, Jordan KA, Monroe JG et al (2008) Tonic B cell antigen receptor signals supply an NF-|[kappa]|B substrate for prosurvival BLyS signaling. Nat Immunol 9:1379

    Article  CAS  PubMed  Google Scholar 

  • Tarlinton D, Lew A (2007) Antigen to the node: B cells go native. Immunity 26:388–390

    Article  CAS  PubMed  Google Scholar 

  • Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Brink R (2004) Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20:785–798

    Article  CAS  PubMed  Google Scholar 

  • Thompson JS, Schneider P, Kalled SL, Wang LC (2000) BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and IS. J Exp Med 192:129–135

    Article  CAS  PubMed  Google Scholar 

  • Tolar P, Sohn HW, Pierce SK (2005) The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer. Nat Immunol 6:1168

    Article  CAS  PubMed  Google Scholar 

  • Tolar P, Hanna J, Krueger P, Pierce SK (2009) The constant region of the membrane immunoglobulin mediates B-cell receptor clustering and signaling in response to membrane antigens. Immunity 30:44–55. doi:10.1016/j.immuni.2008.11.007

    Article  CAS  PubMed  Google Scholar 

  • Wan T, Beavil RL, Fabiane SM, Beavil AJ, Sohi MK, Keown M, Young RJ, Henry AJ, Owens RJ, Gould HJ et al (2002) The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nat Immunol 3:681–686

    Article  CAS  PubMed  Google Scholar 

  • Weber M, Treanor B, Depoil D, Shinohara H, Harwood NE, Hikida M, Kurosaki T, Batista FD (2008) Phospholipase C-{gamma}2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen. J Exp Med 205:1243

    Article  CAS  Google Scholar 

  • Wurzburg BA, Garman SC, Jardetzky TS (2000) Structure of the human IgE-Fc C epsilon 3-C epsilon 4 reveals conformational flexibility in the antibody effector domains. Immunity 13:375–385

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

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

    Pavel Tolar & Susan K. Pierce

Authors
  1. Pavel Tolar
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  2. Susan K. Pierce
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Correspondence to Susan K. Pierce .

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Editors and Affiliations

  1. Allergy & Immunology, RIKEN Research Center for, Suehiro-cho 1-7-22, okohama City, Kanagawa, 230-0045, Japan

    Takashi Saito

  2. London Research Institute, Cancer Research UK, Lincoln's Inn Fields 44, London, WC2A 3PX, United Kingdom

    Facundo D. Batista

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Tolar, P., Pierce, S.K. (2010). A Conformation-Induced Oligomerization Model for B cell Receptor Microclustering and Signaling. In: Saito, T., Batista, F. (eds) Immunological Synapse. Current Topics in Microbiology and Immunology, vol 340. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-03858-7_8

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