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:

Transcriptional regulation of memory B cell differentiation

Nature Reviews Immunology volume 21, pages 209–220 (2021)Cite this article

Subjects

Abstract

Memory B cells (MBCs) are critical for the rapid development of protective immunity following re-infection. MBCs capable of neutralizing distinct subclasses of pathogens, such as influenza and HIV, have been identified in humans. However, efforts to develop vaccines that induce broadly protective MBCs to rapidly mutating pathogens have not yet been successful. Better understanding of the signals regulating MBC development and function are essential to overcome current challenges hindering successful vaccine development. Here, we discuss recent advancements regarding the signals and transcription factors regulating germinal centre-derived MBC development and function.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Transcriptional regulation of GC B cell commitment.
Fig. 2: Transcriptional regulation of GC B cell maintenance.
Fig. 3: Transcriptional regulation of GC B cell differentiation.
Fig. 4: Models of GC B cell differentiation.

Similar content being viewed by others

References

  1. Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009).

    CAS  PubMed  Google Scholar 

  3. McHeyzer-Williams, L. J., Milpied, P. J., Okitsu, S. L. & McHeyzer-Williams, M. G. Class-switched memory B cells remodel BCRs within secondary germinal centers. Nat. Immunol. 16, 296–305 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Pape, K. A., Taylor, J. J., Maul, R. W., Gearhart, P. J. & Jenkins, M. K. Different B cell populations mediate early and late memory during an endogenous immune response. Science 331, 1203–1207 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Zuccarino-Catania, G. V. et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637 (2014). This study identifies new markers that could identify transcriptionally distinct MBC subsets with differing capacities to differentiate into antibody-secreting cells or GC B cells upon antigen re-encounter.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Weisel, F. J., Zuccarino-Catania, G. V., Chikina, M. & Shlomchik, M. J. A temporal switch in the germinal center determines differential output of memory B and plasma cells. Immunity 44, 116–130 (2016). This paper uses a pulse-labelling approach to show that MBC export from the GC precedes that of plasma cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Shinnakasu, R. et al. Regulated selection of germinal-center cells into the memory B cell compartment. Nat. Immunol. 17, 861–869 (2016). This study proposes an instructive model of MBC development in which weak T cell help predisposes GC B cells to express BACH2 and enter the memory compartment.

    CAS  PubMed  Google Scholar 

  8. Laidlaw, B. J., Duan, L., Xu, Y., Vazquez, S. E. & Cyster, J. G. The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development. Nat. Immunol 21, 1082–1093 (2020). Using CRISPR–Cas9 screening in vivo, this study found that HHEX and TLE3 cooperate to promote MBC development during a viral response.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Purtha, W. E., Tedder, T. F., Johnson, S., Bhattacharya, D. & Diamond, M. S. Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants. J. Exp. Med. 208, 2599–2606 (2011). This study finds that MBCs, but not plasma cells, can recognize previously unencountered stains of the West Nile virus, suggesting that MBCs might be an important component of heterosubtypic immunity.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Andrade, P. et al. Impact of pre-existing dengue immunity on human antibody and memory B cell responses to Zika. Nat. Commun. 10, 938 (2019).

    PubMed  PubMed Central  Google Scholar 

  11. McCarthy, K. R. et al. Memory B cells that cross-react with group 1 and group 2 influenza A viruses are abundant in adult human repertoires. Immunity 48, 174–183.e9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Leach, S. et al. Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection. Int. Immunol. 31, 771–779 (2019).

    CAS  PubMed  Google Scholar 

  13. Benson, M. J. et al. Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals. J. Exp. Med. 206, 2013–2025 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Krishnamurty, A. T. et al. Somatically hypermutated plasmodium-specific IgM+ memory B cells are rapid, plastic, early responders upon malaria rechallenge. Immunity 45, 402–414 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zabel, F. et al. Viral particles drive rapid differentiation of memory B cells into secondary plasma cells producing increased levels of antibodies. J. Immunol. 192, 5499–5508 (2014).

    CAS  PubMed  Google Scholar 

  16. Mesin, L. et al. Restricted clonality and limited germinal center reentry characterize memory B cell reactivation by boosting. Cell 180, 92–106.e11 (2020). This study finds that most MBC clones fail to re-enter the GC during recall responses. Rather, recall GCs tend to consist largely of B cells with no GC experience.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, Y. et al. Germinal center B cells govern their own fate via antibody feedback. J. Exp. Med. 210, 457–464 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Toyama, H. et al. Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17, 329–339 (2002).

    CAS  PubMed  Google Scholar 

  19. Obukhanych, T. V. & Nussenzweig, M. C. T-independent type II immune responses generate memory B cells. J. Exp. Med. 203, 305–310 (2006).

    PubMed  PubMed Central  Google Scholar 

  20. Pritchard, G. H. et al. The development of optimally responsive plasmodium-specific CD73+CD80+IgM+ memory B cells requires intrinsic BCL6 expression but not CD4 TFH cells. Preprint at bioRxiv https://doi.org/10.1101/564351 (2019).

    Article  Google Scholar 

  21. Kenderes, K. J. et al. T-Bet+ IgM memory cells generate multi-lineage effector B cells. Cell Rep. 24, 824–837.e3 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fukuda, T. et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J. Exp. Med. 186, 439–448 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang, C. et al. The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers. Cell Rep. 8, 1497–1508 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Willis, S. N. et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. J. Immunol. 192, 3200–3206 (2011).

    Google Scholar 

  25. Basso, K. et al. Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood 115, 975–984 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Saito, M. et al. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 106, 11294–11299 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, Z. et al. BCL-6 negatively regulates expression of the NF-κB1 p105/p50 subunit. J. Immunol. 174, 205–214 (2004).

    Google Scholar 

  28. Linterman, M. A. et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207, 353–363 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chevrier, S., Kratina, T., Emslie, D., Tarlinton, D. M. & Corcoran, L. M. IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation. Immunol. Cell Biol. https://doi.org/10.1038/icb.2017.71 (2017).

    Article  PubMed  Google Scholar 

  30. Zotos, D. et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365–378 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Avery, D. T. et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J. Exp. Med. 207, 155–171 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ochiai, K. et al. Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38, 918–929 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7, 773–782 (2006).

    CAS  PubMed  Google Scholar 

  34. Willis, S. N. et al. Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism. J. Immunol. 192, 3200–3206 (2014).

    CAS  PubMed  Google Scholar 

  35. Sciammas, R. et al. An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol. Syst. Biol. 7, 495 (2011).

    PubMed  PubMed Central  Google Scholar 

  36. Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280–292 (2007).

    CAS  PubMed  Google Scholar 

  37. Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).

    CAS  PubMed  Google Scholar 

  38. Lee, C. H. et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203, 63–72 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou, J. X. et al. IFN regulatory factor 8 regulates MDM2 in germinal center B cells. J. Immunol. 183, 3188–3194 (2009).

    CAS  PubMed  Google Scholar 

  40. Yoon, J. et al. Interferon regulatory factor 8 (IRF8) interacts with the B cell lymphoma 6 (BCL6) corepressor BCOR. J. Biol. Chem. 289, 34250–34257 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Carotta, S. et al. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J. Exp. Med. 211, 2169–2181 (2014).

    PubMed  PubMed Central  Google Scholar 

  42. Wang, H. et al. Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses. Proc. Natl Acad. Sci. USA 116, 9511–9520 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Schubart, D. B., Rolink, A., Kosco-Vilbois, M. H., Botteri, F. & Matthias, P. B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature 383, 538–542 (1996).

    CAS  PubMed  Google Scholar 

  44. Kim, U. et al. The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes. Nature 383, 542–547 (1996).

    CAS  PubMed  Google Scholar 

  45. Corcoran, L. et al. Oct2 and Obf1 as facilitators of B:T cell collaboration during a humoral immune response. Front. Immunol. 5, 108 (2014).

    PubMed  PubMed Central  Google Scholar 

  46. Karnowski, A. et al. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J. Exp. Med. 209, 2049–2064 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bartholdy, B. et al. The Ets factor Spi-B is a direct critical target of the coactivator OBF-1. Proc. Natl Acad. Sci. USA 103, 11665–11670 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Garrett-Sinha, L. A. et al. PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction. Immunity 10, 399–408 (1999).

    CAS  PubMed  Google Scholar 

  49. Su, G. H. et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. EMBO J. 16, 7118–7129 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Willis, S. N. et al. Environmental sensing by mature B cells is controlled by the transcription factors PU.1 and SpiB. Nat. Commun. 8, 1426 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. Calado, D. P. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat. Immunol. 13, 1092–1100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dominguez-Sola, D. et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat. Immunol. 13, 1083–1091 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tanaka, H. et al. E2F1 and c-Myc potentiate apoptosis through inhibition of NF-κB activity that facilitates MnSOD-mediated ROS elimination. Mol. Cell 9, 1017–1029 (2002).

    CAS  PubMed  Google Scholar 

  54. Béguelin, W. et al. EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb–E2F1 feedback loop. Nat. Commun. 8, 877 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. Brescia, P. et al. MEF2B instructs germinal center development and acts as an oncogene in B cell lymphomagenesis. Cancer Cell 34, 453–465.e9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wilker, P. R. et al. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat. Immunol. 9, 603–612 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Khiem, D., Cyster, J. G., Schwarz, J. J. & Black, B. L. A p38 MAPK–MEF2C pathway regulates B-cell proliferation. Proc. Natl Acad. Sci. USA 105, 17067–17072 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ying, C. Y. et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat. Immunol. 14, 1084–1092 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kwon, K. et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity 28, 751–762 (2008).

    CAS  PubMed  Google Scholar 

  60. Wöhner, M. et al. Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development. J. Exp. Med. 213, 1201–1221 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. Gloury, R. et al. Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development. J. Exp. Med. 213, 1095–1111 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, S. et al. Id3 orchestrates germinal center B cell development. Mol. Cell. Biol. 36, 2543–2552 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Green, M. R. et al. Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program. Proc. Natl Acad. Sci. USA 108, 2873–2878 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Vilagos, B. et al. Essential role of EBF1 in the generation and function of distinct mature B cell types. J. Exp. Med. 209, 775–792 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Gyory, I. et al. Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells. Genes. Dev. 26, 668–682 (2012).

    PubMed  PubMed Central  Google Scholar 

  66. Huang, C., Geng, H., Boss, I., Wang, L. & Melnick, A. Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation. Blood 123, 1012–1020 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000).

    CAS  PubMed  Google Scholar 

  68. Reljic, R., Wagner, S. D., Peakman, L. J. & Fearon, D. T. Suppression of signal transducer and activator of transcription 3-dependent B lymphocyte terminal differentiation by BCL-6. J. Exp. Med. 192, 1841–1848 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Polo, J. M., Ci, W., Licht, J. D. & Melnick, A. Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B cells. Blood 112, 644–651 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Niu, H., Ye, B. H. & Dalla-Favera, R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes. Dev. 12, 1953–1961 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang, T.-T. et al. Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help. eLife 6, e19552 (2017).

    PubMed  PubMed Central  Google Scholar 

  72. Ise, W. et al. T follicular helper cell-germinal center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate. Immunity 48, 702–715.e4 (2018).

    CAS  PubMed  Google Scholar 

  73. Weinstein, J. S. et al. TFH cells progressively differentiate to regulate the germinal center response. Nat. Immunol. 17, 1197–1205 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Li, X. et al. Cbl ubiquitin ligases control B cell exit from the germinal-center reaction. Immunity 48, 530–541.e6 (2018).

    CAS  PubMed  Google Scholar 

  75. Davidzohn, N. et al. Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers. J. Exp. Med. 217, 26648 (2019).

    Google Scholar 

  76. Sohn, H. W., Gu, H. & Pierce, S. K. Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J. Exp. Med. 197, 1511–1524 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ly, A. et al. Transcription factor T-bet in B cells modulates germinal center polarization and antibody affinity maturation in response to malaria. Cell Rep. 29, 2257–2269.e6 (2019).

    CAS  PubMed  Google Scholar 

  78. Guthmiller, J. J., Graham, A. C., Zander, R. A., Pope, R. L. & Butler, N. S. Cutting edge: IL-10 is essential for the generation of germinal center B cell responses and anti-plasmodium humoral immunity. J. Immunol. 198, 617–622 (2017).

    CAS  PubMed  Google Scholar 

  79. Rubtsova, K. et al. B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. J. Clin. Invest. 127, 1392–1404 (2017).

    PubMed  PubMed Central  Google Scholar 

  80. Jackson, S. W. et al. B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J. Exp. Med. 213, 733–750 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sander, S. et al. PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity 43, 1075–1086 (2015).

    CAS  PubMed  Google Scholar 

  82. Dominguez-Sola, D. et al. The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 43, 1064–1074 (2015).

    CAS  PubMed  Google Scholar 

  83. Inoue, T. et al. The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. J. Exp. Med. 214, 1181–1198 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bannard, O. et al. Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection. Immunity 39, 912–924 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Albright, A. R. et al. TGFβ signaling in germinal center B cells promotes the transition from light zone to dark zone. J. Exp. Med. 216, 2531–2545 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Laidlaw, B. J. et al. Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Sci. Immunol. 2, eaan4767 (2017).

    PubMed  PubMed Central  Google Scholar 

  87. Koike, T., Harada, K., Horiuchi, S. & Kitamura, D. The quantity of CD40 signaling determines the differentiation of B cells into functionally distinct memory cell subsets. eLife 8, e44245 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ise, W. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat. Immunol. 12, 536–543 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Finkin, S., Hartweger, H., Oliveira, T. Y., Kara, E. E. & Nussenzweig, M. C. Protein amounts of the MYC transcription factor determine germinal center B cell division capacity. Immunity 51, 324–336.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Chen, C. et al. Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection. J. Exp. Med. 215, 1437–1448 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Toboso-Navasa, A. et al. Restriction of memory B cell differentiation at the germinal center B cell positive selection stage. J. Exp. Med. 217, 943 (2020).

    Google Scholar 

  92. Chou, C. et al. The transcription factor AP4 mediates resolution of chronic viral infection through amplification of germinal center B cell responses. Immunity 45, 570–582 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Luo, W., Weisel, F. & Shlomchik, M. J. B cell receptor and CD40 signaling are rewired for synergistic induction of the c-Myc transcription factor in germinal center B cells. Immunity 48, 313–326.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gallagher, E. et al. Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat. Immunol. 8, 57–63 (2006).

    PubMed  Google Scholar 

  95. Heise, N. et al. Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. J. Exp. Med. 211, 2103–2118 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Grumont, R. J. & Gerondakis, S. Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor-κB. J. Exp. Med. 191, 1281–1292 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Grumont, R. J., Strasser, A. & Gerondakis, S. B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-κB regulated c-myc transcription. Mol. Cell 10, 1283–1294 (2002).

    CAS  PubMed  Google Scholar 

  98. De Silva, N. S. et al. Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development. Proc. Natl Acad. Sci. USA 113, 9063–9068 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Luo, W. et al. The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells. Nat. Immunol. 20, 736–746 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhu, Z., Shukla, A., Ramezani-Rad, P., Apgar, J. R. & Rickert, R. C. The AKT isoforms 1 and 2 drive B cell fate decisions during the germinal center response. Life Sci. Alliance 2, e201900506 (2019).

    PubMed  PubMed Central  Google Scholar 

  101. Ersching, J. et al. Germinal center selection and affinity maturation require dynamic regulation of mTORC1 kinase. Immunity 46, 1045–1058.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Raybuck, A. L. et al. B cell-intrinsic mTORC1 promotes germinal center-defining transcription factor gene expression, somatic hypermutation, and memory B cell generation in humoral immunity. J. Immunol. 200, 2627–2639 (2018).

    CAS  PubMed  Google Scholar 

  103. Kometani, K. et al. Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation. Immunity 39, 136–147 (2013).

    CAS  PubMed  Google Scholar 

  104. Mayer, C. T. et al. The microanatomic segregation of selection by apoptosis in the germinal center. Science 358, eaao2602 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. Stewart, I., Radtke, D., Phillips, B., McGowan, S. J. & Bannard, O. Germinal center B cells replace their antigen receptors in dark zones and fail light zone entry when immunoglobulin gene mutations are damaging. Immunity 49, 477–489.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Tamahara, T. et al. The mTOR–Bach2 cascade controls cell cycle and class switch recombination during B cell differentiation. Mol. Cell. Biol. 37, e00418-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. Miura, Y. et al. Bach2 promotes B cell receptor-induced proliferation of B lymphocytes and represses cyclin-dependent kinase inhibitors. J. Immunol. 200, 2882–2893 (2018).

    CAS  PubMed  Google Scholar 

  108. Fischer, S. F. et al. Proapoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody-forming cells. Blood 110, 3978–3984 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Smith, K. G., Weiss, U., Rajewsky, K., Nossal, G. J. & Tarlinton, D. M. Bcl-2 increases memory B cell recruitment but does not perturb selection in germinal centers. Immunity 1, 803–813 (1994).

    CAS  PubMed  Google Scholar 

  110. Laidlaw, B. J. et al. The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells. J. Exp. Med. 214, 639–649 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Wang, Y. et al. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat. Immunol. 18, 921–930 (2017).

    CAS  PubMed  Google Scholar 

  112. Suan, D. et al. CCR6 defines memory B cell precursors in mouse and human germinal centers, revealing light-zone location and predominant low antigen affinity. Immunity 47, 1142–1153.e4 (2017). Laidlaw et al. (J. Exp. Med., 2017), Wang et al. (2017) and Suan et al. identify and characterize MBC precursors residing in the light zone of the GC in mice and humans.

    CAS  PubMed  Google Scholar 

  113. Kuo, T. C. et al. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J. Exp. Med. 204, 819–830 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Hatzi, K. et al. A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Rep. 4, 578–588 (2013).

    CAS  PubMed  Google Scholar 

  115. Bhattacharya, D. et al. Transcriptional profiling of antigen-dependent murine B cell differentiation and memory formation. J. Immunol. 179, 6808–6819 (2007).

    CAS  PubMed  Google Scholar 

  116. Xing, S. et al. Tle corepressors are differentially partitioned to instruct CD8+ T cell lineage choice and identity. J. Exp. Med. 215, 2211–2226 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Jangal, M. et al. The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes. Nucleic Acids Res. 42, 11339–11348 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Takatsuka, S. et al. IL-9 receptor signaling in memory B cells regulates humoral recall responses. Nat. Immunol. 19, 1025–1034 (2018).

    CAS  PubMed  Google Scholar 

  119. Jash, A. et al. ZBTB32 restricts the duration of memory B cell recall responses. J. Immunol. 197, 1159–1168 (2016).

    CAS  PubMed  Google Scholar 

  120. Bernasconi, N. L., Onai, N. & Lanzavecchia, A. A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101, 4500–4504 (2003).

    CAS  PubMed  Google Scholar 

  121. Onodera, T. Whole-virion influenza vaccine recalls an early burst of high-affinity memory B cell response through TLR signaling. J. Immunol. 196, 4172–4184 (2016).

    CAS  PubMed  Google Scholar 

  122. Lutz, J. et al. Reactivation of IgG-switched memory B cells by BCR-intrinsic signal amplification promotes IgG antibody production. Nat. Commun. 6, 8575 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Thomas, M. J., Klein, U., Lygeros, J. & Rodríguez Martínez, M. A probabilistic model of the germinal center reaction. Front. Immunol. 10, 689 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Wang, P., Shih, C.-M., Qi, H. & Lan, Y.-H. A stochastic model of the germinal center integrating local antigen competition, individualistic T–B interactions, and B cell receptor signaling. J. Immunol. 197, 1169–1182 (2016).

    CAS  PubMed  Google Scholar 

  125. Vikstrom, I. et al. Mcl-1 is essential for germinal center formation and B cell memory. Science 330, 1095–1099 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Barnett, B. E. et al. Asymmetric B cell division in the germinal center reaction. Science 335, 342–344 (2012).

    CAS  PubMed  Google Scholar 

  127. Lin, W.-H. W. et al. Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep. https://doi.org/10.1016/j.celrep.2015.10.072 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Duffy, K. R. et al. Activation-induced B cell fates are selected by intracellular stochastic competition. Science 335, 338–341 (2012).

    CAS  PubMed  Google Scholar 

  129. Taylor, J. J., Pape, K. A., Steach, H. R. & Jenkins, M. K. Humoral immunity. Apoptosis and antigen affinity limit effector cell differentiation of a single naïve B cell. Science 347, 784–787 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Tas, J. M. J. et al. Visualizing antibody affinity maturation in germinal centers. Science 351, 1048–1054 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Allie, S. R. et al. The establishment of resident memory B cells in the lung requires local antigen encounter. Nat. Immunol. 20, 97–108 (2019). This study finds that MBCs develop in the lungs after influenza infection and rapidly differentiate into local antibody-secreting cells upon challenge infection.

    CAS  PubMed  Google Scholar 

  132. Adachi, Y. et al. Distinct germinal center selection at local sites shapes memory B cell response to viral escape. J. Exp. Med. 212, 1709–1723 (2015). This study finds that MBCs in the lungs have an elevated fraction of cross-reactive clones relative to cells in the secondary lymphoid organs after influenza virus infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Sungalee, S. et al. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression. J. Clin. Invest. 124, 5337–5351 (2014).

    PubMed  PubMed Central  Google Scholar 

  134. Schmitz, R. et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 378, 1396–1407 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Chapuy, B. et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat. Med. 24, 679–690 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Venturutti, L. et al. TBL1XR1 mutations drive extranodal lymphoma by inducing a pro-tumorigenic memory fate. Cell https://doi.org/10.1016/j.cell.2020.05.049 (2020). This paper reports that a subset of B cell lymphoma is driven by mutations that bias cells to develop into immature MBCs.

    Article  PubMed  PubMed Central  Google Scholar 

  137. He, J.-S. et al. IgG1 memory B cells keep the memory of IgE responses. Nat. Commun. 8, 641 (2017).

    PubMed  PubMed Central  Google Scholar 

  138. Asrat, S. et al. Chronic allergen exposure drives accumulation of long-lived IgE plasma cells in the bone marrow, giving rise to serological memory. Sci. Immunol. 5, eaav8402 (2020).

    CAS  PubMed  Google Scholar 

  139. Gowthaman, U. et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science 365, eaaw6433 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Sayegh, C. E., Quong, M. W., Agata, Y. & Murre, C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat. Immunol. 4, 586–593 (2003).

    CAS  PubMed  Google Scholar 

  141. Gonda, H. et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198, 1427–1437 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Tomayko, M. M., Steinel, N. C., Anderson, S. M. & Shlomchik, M. J. Cutting edge: hierarchy of maturity of murine memory B cell subsets. J. Immunol. 185, 7146–7150 (2010).

    CAS  PubMed  Google Scholar 

  143. Onodera, T. et al. Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc. Natl Acad. Sci. USA 109, 2485–2490 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Lindner, C. et al. Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota. Nat. Immunol. 16, 880–888 (2015).

    CAS  PubMed  Google Scholar 

  145. Bar-Or, A. et al. Immunological memory: contribution of memory B cells expressing costimulatory molecules in the resting state. J. Immunol. 167, 5669–5677 (2001).

    CAS  PubMed  Google Scholar 

  146. Weisel, F. & Shlomchik, M. Memory B cells of mice and humans. Annu. Rev. Immunol. 35, 255–284 (2017).

    CAS  PubMed  Google Scholar 

  147. Seifert, M. et al. 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 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Siewe, B., Nipper, A. J., Sohn, H., Stapleton, J. T. & Landay, A. FcRL4 expression identifies a pro-inflammatory B cell subset in viremic HIV-infected subjects. Front. Immunol. 8, 117 (2017).

    Google Scholar 

  149. Naradikian, M. S. et al. Cutting edge: IL-4, IL-21, and IFN-γ interact to govern T-bet and CD11c expression in TLR-activated B cells. J. Immunol. 197, 1023–1028 (2016).

    CAS  PubMed  Google Scholar 

  150. Yates, J. L., Racine, R., McBride, K. M. & Winslow, G. M. T Cell–Dependent IgM Memory B Cells generated during bacterial infection are required for IgG responses to antigen challenge. J. Immunol. 191, 1240–1249 (2013).

    CAS  PubMed  Google Scholar 

  151. Jenks, S. A. et al. Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity 49, 725–739.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Du, S. W. et al. Functional characterization of CD11c+ age-associated B cells as memory B cells. J. Immunol. 203, 2817–2826 (2019).

    CAS  PubMed  Google Scholar 

  153. Kim, C. C., Baccarella, A. M., Bayat, A., Pepper, M. & Fontana, M. F. FCRL5+ memory B cells exhibit robust recall responses. Cell Rep. 27, 1446–1460.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Peng, S. L., Szabo, S. J. & Glimcher, L. H. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc. Natl Acad. Sci. USA 99, 5545–5550 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Johnson, J. L. et al. The transcription factor T-bet resolves memory B cell subsets with distinct tissue distributions and antibody specificities in mice and humans. Immunity 52, 841–855.e6 (2020).

    Google Scholar 

  156. Piovesan, D. et al. c-Myb regulates the T-bet-dependent differentiation program in B cells to coordinate antibody responses. Cell Rep. 19, 461–470 (2017).

    CAS  PubMed  Google Scholar 

  157. Stone, S. L. et al. T-bet transcription factor promotes antibody-secreting cell differentiation by limiting the inflammatory effects of IFN-γ on B cells. Immunity 50, 1172–1187.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Rubtsova, K., Rubtsov, A. V., van Dyk, L. F., Kappler, J. W. & Marrack, P. T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc. Natl Acad. Sci. USA 110, E3216–E3224 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Brian J. Laidlaw

  2. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA

    Jason G. Cyster

  3. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA

    Jason G. Cyster

Authors
  1. Brian J. Laidlaw
    View author publications

    Search author on:PubMed Google Scholar

  2. Jason G. Cyster
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Brian J. Laidlaw.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thank the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Germinal centre

A structure that forms in the B cell follicle of secondary lymphoid organs during an immune response in which B cells engage with antigen and compete for signals necessary for their survival, proliferation and differentiation into plasma cells or memory B cells.

Somatic hypermutation

A cellular process in which proliferating B cells accumulate mutations in antibody complementarity-determining regions, potentially impacting their ability to recognize antigen.

Plasma cells

Large, terminally differentiated B lymphocytes that continually secrete antibodies and are also known as antibody-secreting cells.

Recall responses

Immune responses in which memory B cells re-encounter their cognate antigen and differentiate into antibody-secreting cells or re-enter the germinal centre to undergo further diversification.

Affinity maturation

The process by which germinal centre B cells increase their affinity for antigen during an immune response as a result of competition for a limiting amount of CD40L-expressing follicular helper T cells.

Cross-reactive viral antigens

Viral protein sequences that are conserved between different strains of a pathogen.

Heterosubtypic immunity

Immunity in which lymphocytes are generated that can protect against multiple subtypes of a pathogen.

MBC clones

Memory B cells (MBCs) with a particular specificity for antigen.

Secondary GC response

A new germinal centre (GC) that forms against an immunogen or pathogen that the host previously encountered and developed immunological memory against.

Naive B cells

B cells that have not been exposed to antigen.

Class-switched

A cellular process in which proliferating B cells have rearranged their constant region genes to switch from expressing one class of immunoglobulin to another, without altering their antigen specificity.

Dark zone

The compartment of the germinal centre in which B cells proliferate and undergo somatic hypermutation, which contains a network of stromal cells producing the CXCR4 ligand CXCL12.

Light zone

The compartment of the germinal centre in which B cells capture antigen presented by follicular dendritic cells and compete to present antigen to follicular helper T cells in order to receive signals necessary for their continued survival, proliferation and differentiation.

Type 2 immune responses

An immune response that typically occurs in response to extracellular bacteria, parasites, toxins or allergens. Generally characterized by the production of IL-4, IL-5 and IL-13.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laidlaw, B.J., Cyster, J.G. Transcriptional regulation of memory B cell differentiation. Nat Rev Immunol 21, 209–220 (2021). https://doi.org/10.1038/s41577-020-00446-2

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41577-020-00446-2

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