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The Memory Function of the B Cell Antigen Receptor

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B Cell Receptor Signaling

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 393))

Abstract

Activated B lymphocytes preserve their antigen experience by differentiating into long-lived pools of antibody-secreting plasma cells or various types of memory B cells (MBCs). The former population constantly produces serum immunoglobulins with sufficient specificity and affinity to thwart infections with recurrent pathogens. By contrast, memory B cell populations retain their antigen receptors on the cell surface and hence need pathogen-induced differentiation steps before they can actively contribute to host defense. The terminal differentiation of MBCs into antibody-secreting plasma cells is hallmarked by the absence of the lag phase characteristic for primary antibody responses. Moreover, secondary antibody responses are predominantly driven by MBCs that bear an antigen receptor of the IgG class on their surface although IgM-positive memory populations exist as well. These fundamental principles of B cell memory were enigmatic for decades. Only recently, we have begun to understand the underlying mechanisms. This review summarizes our current understanding of how different subpopulations of MBCs are generated during primary immune responses and how their functional heterogeneity on antigen recall is controlled by different signaling capabilities of B cell antigen receptor (BCR) isotypes and by the nature of the antigen.

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References

  • Achatz G, Nitschke L, Lamers MC (1997) Effect of transmembrane and cytoplasmic domains of IgE on the IgE response. Science 276:409–411

    Article  CAS  Google Scholar 

  • Ackermann JA, Radtke D, Maurberger A, Winkler TH, Nitschke L (2011) Grb2 regulates B-cell maturation, B-cell memory responses and inhibits B-cell Ca2+ signalling. EMBO J 30:1621–1633

    Article  CAS  Google Scholar 

  • Anderson SM, Tomayko MM, Ahuja A, Haberman AM, Shlomchik MJ (2007) New markers for murine memory B cells that define mutated and unmutated subsets. J Exp Med 204:2103–2114

    Article  CAS  Google Scholar 

  • Benson MJ, Elgueta R, Schpero W, Molloy M, Zhang W, Usherwood E, Noelle RJ (2009) Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals. J Exp Med 206:2013–2025

    Article  CAS  Google Scholar 

  • Casola S, Cattoretti G, Uyttersprot N, Koralov SB, Seagal J, Hao Z, Waisman A, Egert A, Ghitza D, Rajewsky K (2006) Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting. Proc Natl Acad Sci USA 103:7396–7401

    Google Scholar 

  • Castellino F, Galli G, Del Giudice G, Rappuoli R (2009) Generating memory with vaccination. Eur J Immunol 39:2100–2105

    Article  CAS  Google Scholar 

  • Chan TD, Gatto D, Wood K, Camidge T, Basten A, Brink R (2009) Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J Immunol 183:3139–3149

    Article  CAS  Google Scholar 

  • Coffman RL, Cohn M (1977) The class of surface immunoglobulin on virgin and memory B lymphocytes. J Immunol 118:1806–1815

    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  Google Scholar 

  • Dogan I, Bertocci B, Vilmont V, Delbos F, Megret J, Storck S, Reynaud CA, Weill JC (2009) Multiple layers of B cell memory with different effector functions. Nat Immunol 10:1292–1299

    Article  CAS  Google Scholar 

  • Durandy A, Revy P, Imai K, Fischer A (2005) Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev 203:67–79

    Article  CAS  Google Scholar 

  • Engels N, Konig LM, Heemann C, Lutz J, Tsubata T, Griep S, Schrader V, Wienands J (2009) Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells. Nat Immunol 10:1018–1025

    Article  CAS  Google Scholar 

  • Engels N, Konig LM, Schulze W, Radtke D, Vanshylla K, Lutz J, Winkler TH, Nitschke L, Wienands J (2014) The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module. Nat Commun 5:5456

    Google Scholar 

  • Engels N, Wienands J (2011) The signaling tool box for tyrosine-based costimulation of lymphocytes. Curr Opin Immunol 23:324–329

    Article  CAS  Google Scholar 

  • Fecteau JF, Cote G, Neron S (2006) A new memory CD27-IgG+ B cell population in peripheral blood expressing VH genes with low frequency of somatic mutation. J Immunol 177:3728–3736

    Article  CAS  Google Scholar 

  • Hawkins ED, Oliaro J, Kallies A, Belz GT, Filby A, Hogan T, Haynes N, Ramsbottom KM, Van Ham V, Kinwell T, Seddon B, Davies D, Tarlinton D, Lew AM, Humbert PO, Russell SM (2013) Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity. Nat Commun 4:1801

    Google Scholar 

  • Hebeis BJ, Klenovsek K, Rohwer P, Ritter U, Schneider A, Mach M, Winkler TH (2004) Activation of virus-specific memory B cells in the absence of T cell help. J Exp Med 199:593–602

    Article  CAS  Google Scholar 

  • Heyman B (2003) Feedback regulation by IgG antibodies. Immunol Lett 88:157–161

    Article  CAS  Google Scholar 

  • Hikida M, Casola S, Takahashi N, Kaji T, Takemori T, Rajewsky K, Kurosaki T (2009) PLC-gamma2 is essential for formation and maintenance of memory B cells. J Exp Med 206:681–689

    Article  CAS  Google Scholar 

  • Inamine A, Takahashi Y, Baba N, Miyake K, Tokuhisa T, Takemori T, Abe R (2005) Two waves of memory B-cell generation in the primary immune response. Int Immunol 17:581–589

    Article  CAS  Google Scholar 

  • Kaisho T, Schwenk F, Rajewsky K (1997) The roles of gamma 1 heavy chain membrane expression and cytoplasmic tail in IgG1 responses. Science 276:412–415

    Article  CAS  Google Scholar 

  • Kaji T, Ishige A, Hikida M, Taka J, Hijikata A, Kubo M, Nagashima T, Takahashi Y, Kurosaki T, Okada M, Ohara O, Rajewsky K, Takemori T (2012) Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. J Exp Med 209:2079–2097

    Article  CAS  Google Scholar 

  • Klaus GG, Humphrey JH, Kunkl A, Dongworth DW (1980) The follicular dendritic cell: its role in antigen presentation in the generation of immunological memory. Immunol Rev 53:3–28

    Article  CAS  Google Scholar 

  • Klein U, Kuppers R, Rajewsky K (1997) Evidence for a large compartment of IgM-expressing memory B cells in humans. Blood 89:1288–1298

    Google Scholar 

  • Klein U, Rajewsky K, Kuppers R (1998) Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med 188:1679–1689

    Article  CAS  Google Scholar 

  • Klinman NR (1972) The mechanism of antigenic stimulation of primary and secondary clonal precursor cells. J Exp Med 136:241–260

    Article  CAS  Google Scholar 

  • Klinman NR, Doughty RA (1973) Hapten-specific stimulation of secondary B cells independent of T cells. J Exp Med 138:473–478

    Article  CAS  Google Scholar 

  • Kurosaki T, Aiba Y, Kometani K, Moriyama S, Takahashi Y (2010) Unique properties of memory B cells of different isotypes. Immunol Rev 237:104–116

    Article  CAS  Google Scholar 

  • Liu W, Chen E, Zhao XW, Wan ZP, Gao YR, Davey A, Huang E, Zhang L, Crocetti J, Sandoval G, Joyce MG, Miceli C, Lukszo J, Aravind L, Swat W, Brzostowski J, Pierce SK (2012) The scaffolding protein synapse-associated protein 97 is required for enhanced signaling through isotype-switched IgG memory B cell receptors. Sci Sig 5:ra54

    Article  Google Scholar 

  • Liu W, Meckel T, Tolar P, Sohn HW, Pierce SK (2010a) Antigen affinity discrimination is an intrinsic function of the B cell receptor. J Exp Med 207:1095–1111

    Article  CAS  Google Scholar 

  • Liu W, Meckel T, Tolar P, Sohn HW, Pierce SK (2010b) Intrinsic properties of immunoglobulin IgG1 isotype-switched B cell receptors promote microclustering and the initiation of signaling. Immunity 32:778–789

    Article  CAS  Google Scholar 

  • McHeyzer-Williams LJ, McHeyzer-Williams MG (2005) Antigen-specific memory B cell development. Annu Rev Immunol 23:487–513

    Article  CAS  Google Scholar 

  • Obukhanych TV, Nussenzweig MC (2006) T-independent type II immune responses generate memory B cells. J Exp Med 203:305–310

    Article  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  Google Scholar 

  • Pape KA, Taylor JJ, Maul RW, Gearhart PJ, Jenkins MK (2011) Different B cell populations mediate early and late memory during an endogenous immune response. Science 331:1203–1207

    Article  CAS  Google Scholar 

  • Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R (2006) Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203:1081–1091

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Reynaud CA, Descatoire M, Dogan I, Huetz F, Weller S, Weill JC (2012) Cellular and molecular life sciences. IgM memory B cells: a mouse/human paradox. CMLS 69:1625–1634

    Article  CAS  Google Scholar 

  • Sallusto F, Lanzavecchia A, Araki K, Ahmed R (2010) From vaccines to memory and back. Immunity 33:451–463

    Article  CAS  Google Scholar 

  • Schittek B, Rajewsky K (1990) Maintenance of B-cell memory by long-lived cells generated from proliferating precursors. Nature 346:749–751

    Article  CAS  Google Scholar 

  • Seifert M, Przekopowitz M, Taudien S, Lollies A, Ronge V, Drees B, Lindemann M, Hillen U, Engler H, Singer BB, Kuppers R (2015) Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions. Proc Natl Acad Sci USA 112:E546–E555

    Article  CAS  Google Scholar 

  • Stavnezer J, Schrader CE (2014) IgH chain class switch recombination: mechanism and regulation. Novel role of the Ras cascade in memory B cell response. J Immunol 193:5370–5378

    Article  CAS  Google Scholar 

  • Takahashi Y, Inamine A, Hashimoto S, Haraguchi S, Yoshioka E, Kojima N, Abe R, Takemori T (2005) Novel role of the Ras cascade in memory B cell response. Immunity 23:127–138

    Article  CAS  Google Scholar 

  • Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K (2014) Generation of memory B cells inside and outside germinal centers. Eur J Immunol 44:1258–1264

    Article  CAS  Google Scholar 

  • Tangye SG, Good KL (2007) Human IgM+CD27+ B cells: memory B cells or “memory” B cells?. J Immunol 179:13–19

    Article  CAS  Google Scholar 

  • Tangye SG, Liu YJ, Aversa G, Phillips JH, de Vries JE (1998) Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med 188:1691–1703

    Article  CAS  Google Scholar 

  • Tangye SG, Tarlinton DM (2009) Memory B cells: effectors of long-lived immune responses. Eur J Immunol 39:2065–2075

    Article  CAS  Google Scholar 

  • Taylor JJ, Jenkins MK, Pape KA (2012a) Heterogeneity in the differentiation and function of memory B cells. Trends Immunol 33:590–597

    Article  CAS  Google Scholar 

  • Taylor JJ, Pape KA, Jenkins MK (2012b) A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med 209:597–606

    Article  CAS  Google Scholar 

  • Thorbecke G, Lerman SP (1976) Germinal centers and their role in immune responses. Adv Exp Med Biol 73 PT-A:83–100

    Google Scholar 

  • Tomayko MM, Steinel NC, Anderson SM, Shlomchik MJ (2010) Cutting edge: Hierarchy of maturity of murine memory B cell subsets. J Immunol 185:7146–7150

    Article  CAS  Google Scholar 

  • Toyama H, Okada S, Hatano M, Takahashi Y, Takeda N, Ichii H, Takemori T, Kuroda Y, Tokuhisa T (2002) Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17:329–339

    Article  CAS  Google Scholar 

  • Uhr JW (1964) The Heterogeneity of the Immune Response. Science 145:457–464

    Article  CAS  Google Scholar 

  • Vinuesa CG, Linterman MA, Goodnow CC, Randall KL (2010) T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol Rev 237:72–89

    Article  CAS  Google Scholar 

  • Vitetta ES, Berton MT, Burger C, Kepron M, Lee WT, Yin XM (1991) Memory B and T cells. Annu Rev Immunol 9:193–217

    Article  CAS  Google Scholar 

  • Weill JC, Weller S, Reynaud CA (2009) Human marginal zone B cells. Annu Rev Immunol 27:267–285

    Article  CAS  Google Scholar 

  • Weisel FJ, Appelt UK, Schneider AM, Horlitz JU, van Rooijen N, Korner H, Mach M, Winkler TH (2010) Unique requirements for reactivation of virus-specific memory B lymphocytes. J Immunol 185:4011–4021

    Article  CAS  Google Scholar 

  • Winslow MM, Gallo EM, Neilson JR, Crabtree GR (2006) The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24:141–152

    Article  CAS  Google Scholar 

  • Yasuda T, Kometani K, Takahashi N, Imai Y, Aiba Y, Kurosaki T (2011) ERKs induce expression of the transcriptional repressor Blimp-1 and subsequent plasma cell differentiation. Sci Sig 4:ra25

    Article  Google Scholar 

  • Yefenof E, Sanders VM, Uhr JW, Vitetta ES (1986) In vitro activation of murine antigen-specific memory B cells by a T-dependent antigen. J Immunol 137:85–90

    Google Scholar 

  • Yu X, Tsibane T, McGraw PA, House FS, Keefer CJ, Hicar MD, Tumpey TM, Pappas C, Perrone LA, Martinez O, Stevens J, Wilson IA, Aguilar PV, Altschuler EL, Basler CF, Crowe JE Jr (2008) Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 455:532–536

    Article  CAS  Google Scholar 

  • Yuan D, Vitetta ES, Kettman JR (1977) Cell surface immunoglobulin. XX. Antibody responsiveness of subpopulations of B lymphocytes bearing different isotypes. J Exp Med 145:1421–1435

    Article  CAS  Google Scholar 

  • Zhang Y, Meyer-Hermann M, George LA, Figge MT, Khan M, Goodall M, Young SP, Reynolds A, Falciani F, Waisman A, Notley CA, Ehrenstein MR, Kosco-Vilbois M, Toellner KM (2013) Germinal center B cells govern their own fate via antibody feedback. J Exp Med 210:457–464

    Article  CAS  Google Scholar 

  • Zuccarino-Catania GV, Sadanand S, Weisel FJ, Tomayko MM, Meng H, Kleinstein SH, Good-Jacobson KL, Shlomchik MJ (2014) CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat Immunol 15:631–637

    Article  CAS  Google Scholar 

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Acknowledgements

Our work is supported by the Deutsche Forschungsgemeinschaft through projects EN 834/1‐1, EN 834/2‐1 and the TRR 130.

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Authors and Affiliations

  1. Medical Faculty, Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Humboldtallee 34, 37073, Göttingen, Germany

    Jürgen Wienands & Niklas Engels

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  1. Jürgen Wienands
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  2. Niklas Engels
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Correspondence to Jürgen Wienands or Niklas Engels .

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Editors and Affiliations

  1. WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Tomohiro Kurosaki

  2. Cellular and Molecular Immunology, Georg August University Goettingen, Göttingen, Germany

    Jürgen Wienands

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Wienands, J., Engels, N. (2015). The Memory Function of the B Cell Antigen Receptor. In: Kurosaki, T., Wienands, J. (eds) B Cell Receptor Signaling. Current Topics in Microbiology and Immunology, vol 393. Springer, Cham. https://doi.org/10.1007/82_2015_480

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