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Memory B cells

Nature Reviews Immunology volume 24, pages 5–17 (2024)Cite this article

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Abstract

Recent advances in studies of immune memory in mice and humans have reinforced the concept that memory B cells play a critical role in protection against repeated infections, particularly from variant viruses. Hence, insights into the development of high-quality memory B cells that can generate broadly neutralizing antibodies that bind such variants are key for successful vaccine development. Here, we review the cellular and molecular mechanisms by which memory B cells are generated and how these processes shape the antibody diversity and breadth of memory B cells. Then, we discuss the mechanisms of memory B cell reactivation in the context of established immune memory; the contribution of antibody feedback to this process has now begun to be reappreciated.

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Fig. 1: GC dynamics and memory B cell selection.
Fig. 2: Generation of GC-independent and GC-dependent memory B cells.
Fig. 3: Memory B cell generation from GCs.
Fig. 4: Memory B cell reactivation.

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References

  1. Chappert, P. et al. Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting. Immunity 55, 1872–1890.e9 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Duggal, N. A., Niemiro, G., Harridge, S. D. R., Simpson, R. J. & Lord, J. M. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat. Rev. Immunol. 19, 563–572 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Crotty, S. et al. Cutting edge: long-term B cell memory in humans after smallpox vaccination. J. Immunol. 171, 4969–4973 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Kurosaki, T., Kometani, K. & Ise, W. Memory B cells. Nat. Rev. Immunol. 15, 149–159 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Anderson, S. M., Tomayko, M. M. & Shlomchik, M. J. Intrinsic properties of human and murine memory B cells. Immunol. Rev. 211, 280–294 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Tarlinton, D. & Good-Jacobson, K. Diversity among memory B cells: origin, consequences, and utility. Science 341, 1205–1211 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Wong, R. et al. Affinity-restricted memory B cells dominate recall responses to heterologous flaviviruses. Immunity 53, 1078–1094.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl Med. 7, 316ra192 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Turner, J. S. et al. Human germinal centres engage memory and naive B cells after influenza vaccination. Nature 586, 127–132 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Vergani, S. et al. A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut. Immunity 55, 1829–1842.e6 (2022).

    Article  CAS  PubMed  Google Scholar 

  15. Schiepers, A. et al. Molecular fate-mapping of serum antibody responses to repeat immunization. Nature 615, 482–489 (2023). Together with Turner et al. (2020), this study suggests that boosting with immunogens of sufficient antigenic distance allows naive B cells to enter secondary GC responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morris, D. L. & Rothstein, T. L. Abnormal transcription factor induction through the surface immunoglobulin M receptor of B-1 lymphocytes. J. Exp. Med. 177, 857–861 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Savage, H. P. et al. TLR induces reorganization of the IgM–BCR complex regulating murine B-1 cell responses to infections. eLife 8, e46997 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Patel, P. S., King, R. G. & Kearney, J. F. Pulmonary α-1,3-glucan-specific IgA-secreting B cells suppress the development of cockroach allergy. J. Immunol. 197, 3175–3187 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478–485 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Taylor, J. J., Pape, K. A. & Jenkins, M. K. A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J. Exp. Med. 209, 597–606 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kaji, T. et al. Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. J. Exp. Med. 209, 2079–2097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roco, J. A. et al. Class-switch recombination occurs infrequently in germinal centers. Immunity 51, 337–350.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reboldi, A. et al. IgA production requires B cell interaction with subepithelial dendritic cells in Peyer’s patches. Science 352, aaf4822 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Toellner, K. M., Gulbranson-Judge, A., Taylor, D. R., Sze, D. M. & MacLennan, I. C. Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation. J. Exp. Med. 183, 2303–2312 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hong, S. et al. B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen. Immunity 49, 695–708.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Ise, W. et al. Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells. Proc. Natl Acad. Sci. USA 111, 11792–11797 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Choi, Y. S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932–946 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. DiToro, D. et al. Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. Science 361, eaao2933 (2018).

    Article  PubMed  PubMed Central  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Olatunde, A. C., Hale, J. S. & Lamb, T. J. Cytokine-skewed TFH cells: functional consequences for B cell help. Trends Immunol. 42, 536–550 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Eisenbarth, S. C. et al. CD4+ T cells that help B cells—a proposal for uniform nomenclature. Trends Immunol. 42, 658–669 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, D. et al. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature 517, 214–218 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tangye, S. G. & Warnatz, K. “Are you gonna go my way?” — Decisions at the TFH–B cell interface. Immunity 55, 377–379 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Moriyama, S. et al. Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers. J. Exp. Med. 211, 1297–1305 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Merkenschlager, J. et al. Dynamic regulation of TFH selection during the germinal centre reaction. Nature 591, 458–463 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 naive B cell. Science 347, 784–787 (2015). This study shows that the differentiation fate of individual antigen-specific naive B cells is influenced by BCR affinity for antigen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 

  41. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lingwood, D. et al. Structural and genetic basis for development of broadly neutralizing influenza antibodies. Nature 489, 566–570 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Glaros, V. et al. Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response. Immunity 54, 2005–2023.e10 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Young, C. & Brink, R. The unique biology of germinal center B cells. Immunity 54, 1652–1664 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 40, 413–442 (2022).

    Article  CAS  PubMed  Google Scholar 

  47. Viant, C. et al. Antibody affinity shapes the choice between memory and germinal center B cell fates. Cell 183, 1298–1311.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shinnakasu, R. et al. Regulated selection of germinal-center cells into the memory B cell compartment. Nat. Immunol. 17, 861–869 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Shlomchik, M. J., Luo, W. & Weisel, F. Linking signaling and selection in the germinal center. Immunol. Rev. 288, 49–63 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Quast, I. et al. Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells. Immunity 55, 1414–1430.e15 (2022).

    Article  CAS  PubMed  Google Scholar 

  51. Huse, M., Lillemeier, B. F., Kuhns, M. S., Chen, D. S. & Davis, M. M. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7, 247–255 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kuraoka, M. et al. Complex antigens drive permissive clonal selection in germinal centers. Immunity 44, 542–552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schwickert, T. A., Alabyev, B., Manser, T. & Nussenzweig, M. C. Germinal center reutilization by newly activated B cells. J. Exp. Med. 206, 2907–2914 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Toellner, K. M., Sze, D. M. & Zhang, Y. What are the primary limitations in B-cell affinity maturation, and how much affinity maturation can we drive with vaccination? A role for antibody feedback. Cold Spring Harb. Perspect. Biol. 10, a028795 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Meyer-Hermann, M. Injection of antibodies against immunodominant epitopes tunes germinal centers to generate broadly neutralizing antibodies. Cell Rep. 29, 1066–1073.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Inoue, T. et al. Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees. J. Exp. Med. 220, e20221786 (2023).

    Article  CAS  PubMed  Google Scholar 

  59. Hagglof, T. et al. Continuous germinal center invasion contributes to the diversity of the immune response. Cell 186, 147–161.e15 (2023).

    Article  CAS  PubMed  Google Scholar 

  60. de Carvalho, R. V. H. et al. Clonal replacement sustains long-lived germinal centers primed by respiratory viruses. Cell 186, 131–146.e13 (2023). Together with Hagglof et al. (2023), this study shows that low-affinity naive B cells continuously invade ongoing GCs, progressively replacing the founder clones, whereas rare long-lived founder clones generate highly mutated memory B cells that can be recalled.

    Article  PubMed  Google Scholar 

  61. Sabouri, Z. et al. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc. Natl Acad. Sci. USA 111, E2567–E2575 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Reed, J. H., Jackson, J., Christ, D. & Goodnow, C. C. Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization. J. Exp. Med. 213, 1255–1265 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Burnett, D. L. et al. Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination. Science 360, 223–226 (2018). This study shows evidence that self-reactive BCR undergoes redemption by SHM during GC responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bajic, G. et al. Influenza antigen engineering focuses immune responses to a subdominant but broadly protective viral epitope. Cell Host Microbe 25, 827–835.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sangesland, M. et al. Allelic polymorphism controls autoreactivity and vaccine elicitation of human broadly neutralizing antibodies against influenza virus. Immunity 55, 1693–1709.e8 (2022).

    Article  CAS  PubMed  Google Scholar 

  66. Inoue, T. et al. Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal. J. Exp. Med. 218, e20200866 (2021).

    Article  CAS  PubMed  Google Scholar 

  67. Inoue, T., Moran, I., Shinnakasu, R., Phan, T. G. & Kurosaki, T. Generation of memory B cells and their reactivation. Immunol. Rev. 283, 138–149 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. 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). Together with Wong et al. (2020), Viant et al. (2020) and Shinnakasu et al. (2016), this work shows that the GC B cells with low-affinity BCR favour the memory B cell differentiation fate.

    Article  CAS  PubMed  Google Scholar 

  69. Duan, L. et al. Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation. Immunity 54, 2256–2272.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Schwickert, T. A. et al. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 208, 1243–1252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mesin, L., Ersching, J. & Victora, G. D. Germinal center B cell dynamics. Immunity 45, 471–482 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gitlin, A. D. et al. Independent roles of switching and hypermutation in the development and persistence of B lymphocyte memory. Immunity 44, 769–781 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen, S. T., Oliveira, T. Y., Gazumyan, A., Cipolla, M. & Nussenzweig, M. C. B cell receptor signaling in germinal centers prolongs survival and primes B cells for selection. Immunity 56, 547–561.e7 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Toboso-Navasa, A. et al. Restriction of memory B cell differentiation at the germinal center B cell positive selection stage. J. Exp. Med. 217, e20191933 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Inoue, T., Shinnakasu, R. & Kurosaki, T. Generation of high quality memory B cells. Front. Immunol. 12, 825813 (2021).

    Article  CAS  PubMed  Google Scholar 

  82. Hatzi, K. et al. BCL6 orchestrates TFH cell differentiation via multiple distinct mechanisms. J. Exp. Med. 212, 539–553 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Laidlaw, B. J. & Cyster, J. G. Transcriptional regulation of memory B cell differentiation. Nat. Rev. Immunol. 21, 209–220 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Anderson, S. M., Tomayko, M. M., Ahuja, A., Haberman, A. M. & Shlomchik, M. J. New markers for murine memory B cells that define mutated and unmutated subsets. J. Exp. Med. 204, 2103–2114 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Viant, C. et al. Germinal center-dependent and -independent memory B cells produced throughout the immune response. J. Exp. Med. 218, e20202489 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. Ehrhardt, G. R. et al. Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells. J. Exp. Med. 202, 783–791 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cancro, M. P. Age-associated B cells. Annu. Rev. Immunol. 38, 315–340 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Phalke, S. et al. Molecular mechanisms controlling age-associated B cells in autoimmunity. Immunol. Rev. 307, 79–100 (2022).

    Article  CAS  PubMed  Google Scholar 

  94. Rubtsov, A. V. et al. Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity. Blood 118, 1305–1315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gao, X. & Cockburn, I. A. The development and function of CD11c+ atypical B cells—insights from single cell analysis. Front. Immunol. 13, 979060 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Holla, P. et al. Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity. Sci. Adv. 7, eabg8384 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ambegaonkar, A. A., Holla, P., Dizon, B. L., Sohn, H. & Pierce, S. K. Atypical B cells in chronic infectious diseases and systemic autoimmunity: puzzles with many missing pieces. Curr. Opin. Immunol. 77, 102227 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dominguez Conde, C. et al. Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science 376, eabl5197 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gao, X. et al. ZEB2 regulates the development of CD11c+ atypical B cells. Preprint at bioRxiv https://doi.org/10.1101/2022.09.01.506173 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Gu, S. et al. The transcription factor Zeb2 drives differentiation of age-associated B cells. Preprint at bioRxiv https://doi.org/10.1101/2021.07.24.453633 (2021).

    Article  Google Scholar 

  101. Song, W. et al. Development of Tbet- and CD11c-expressing B cells in a viral infection requires T follicular helper cells outside of germinal centers. Immunity 55, 290–307.e5 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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 

  103. Clingan, J. M. & Matloubian, M. B cell-intrinsic TLR7 signaling is required for optimal B cell responses during chronic viral infection. J. Immunol. 191, 810–818 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Walsh, K. B. et al. Toll-like receptor 7 is required for effective adaptive immune responses that prevent persistent virus infection. Cell Host Microbe 11, 643–653 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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, 842–855.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cerutti, A., Cols, M. & Puga, I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat. Rev. Immunol. 13, 118–132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. McGrath, J. J. C., Li, L. & Wilson, P. C. Memory B cell diversity: insights for optimized vaccine design. Trends Immunol. 43, 343–354 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Moran, I. et al. Memory B cells are reactivated in subcapsular proliferative foci of lymph nodes. Nat. Commun. 9, 3372 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Zhang, Y. et al. Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift. Nat. Commun. 13, 2460 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fazilleau, N. et al. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 8, 753–761 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Kuraoka, M. et al. Recall of B cell memory depends on relative locations of prime and boost immunization. Sci. Immunol. 7, eabn5311 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tan, H. X. et al. Inducible bronchus-associated lymphoid tissues (iBALT) serve as sites of B cell selection and maturation following influenza infection in mice. Front. Immunol. 10, 611 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tan, H. X. et al. Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles. Sci. Immunol. 7, eabf5314 (2022).

    Article  CAS  PubMed  Google Scholar 

  117. Gregoire, C. et al. Viral infection engenders bona fide and bystander subsets of lung-resident memory B cells through a permissive mechanism. Immunity 55, 1216–1233.e9 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. MacLean, A. J. et al. Secondary influenza challenge triggers resident memory B cell migration and rapid relocation to boost antibody secretion at infected sites. Immunity 55, 718–733.e8 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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 shows that the secondary GCs during recall responses mostly consist of B cells with no prior GC experience, suggesting a clonality bottleneck for the antibody diversity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Abbott, R. K. et al. Precursor frequency and affinity determine B cell competitive fitness in germinal centers, tested with germline-targeting HIV vaccine immunogens. Immunity 48, 133–146.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  121. Heyman, B. Regulation of antibody responses via antibodies, complement, and Fc receptors. Annu. Rev. Immunol. 18, 709–737 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Smith, T. Active immunity produced by so called balanced or neutral mixtures of diphtheria toxin and antitoxin. J. Exp. Med. 11, 241–256 (1909).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tas, J. M. J. et al. Antibodies from primary humoral responses modulate the recruitment of naive B cells during secondary responses. Immunity 55, 1856–1871.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. McNamara, H. A. et al. Antibody feedback limits the expansion of B cell responses to malaria vaccination but drives diversification of the humoral response. Cell Host Microbe 28, 572–585.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Schaefer-Babajew, D. et al. Antibody feedback regulates immune memory after SARS-CoV-2 mRNA vaccination. Nature 613, 735–742 (2023). Together with Inoue et al. (2023) and Tas et al. (2022), this study suggests the contribution of antibody feedback to B cell responses upon SARS-CoV-2 antigen immunization in mice or mRNA vaccination in humans.

    Article  CAS  PubMed  Google Scholar 

  126. Sette, A. & Crotty, S. Immunological memory to SARS-CoV-2 infection and COVID-19 vaccines. Immunol. Rev. 310, 27–46 (2022).

    Article  CAS  PubMed  Google Scholar 

  127. Roltgen, K. & Boyd, S. D. Antibody and B cell responses to SARS-CoV-2 infection and vaccination. Cell Host Microbe 29, 1063–1075 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sette, A. & Crotty, S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 184, 861–880 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rodda, L. B. et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell 184, 169–183.e17 (2021).

    Article  CAS  PubMed  Google Scholar 

  130. Goel, R. R. et al. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science 374, abm0829 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Rodda, L. B. et al. Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity. Cell 185, 1588–1601.e14 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, Z. et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature 592, 616–622 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Muecksch, F. et al. Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost. Nature 607, 128–134 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cirelli, K. M. et al. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell 177, 1153–1171.e28 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Turner, J. S. et al. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature 596, 109–113 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kim, W. et al. Germinal centre-driven maturation of B cell response to mRNA vaccination. Nature 604, 141–145 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mudd, P. A. et al. SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans. Cell 185, 603–613.e15 (2022).

    Article  CAS  PubMed  Google Scholar 

  138. Lederer, K. et al. Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals. Cell 185, 1008–1024.e15 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Forsell, M. N. E., Kvastad, L., Sedimbi, S. K., Andersson, J. & Karlsson, M. C. I. Regulation of subunit-specific germinal center B cell responses to the HIV-1 envelope glycoproteins by antibody-mediated feedback. Front. Immunol. 8, 738 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Duan, H. et al. Glycan masking focuses immune responses to the HIV-1 CD4-binding site and enhances elicitation of VRC01-class precursor antibodies. Immunity 49, 301–311.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shinnakasu, R. et al. Glycan engineering of the SARS-CoV-2 receptor-binding domain elicits cross-neutralizing antibodies for SARS-related viruses. J. Exp. Med. 218, e20211003 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lee, J. H. et al. Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers. J. Exp. Med. 218, e20201254 (2021).

    Article  CAS  PubMed  Google Scholar 

  143. Li, J., Lu, E., Yi, T. & Cyster, J. G. EBI2 augments TFH cell fate by promoting interaction with IL-2-quenching dendritic cells. Nature 533, 110–114 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank P. D. Burrows for critical reading of the manuscript. This work was supported, in part, by Japan Society for the Promotion of Science KAKENHI (JP21H02749 to T.I., JP22H00450 to T.K.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T.I.) and the Chemo-Sero-Therapeutic Research Institute (to T.I.).

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Authors and Affiliations

  1. Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Takeshi Inoue & Tomohiro Kurosaki

  2. Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

    Tomohiro Kurosaki

  3. Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan

    Tomohiro Kurosaki

  4. Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan

    Tomohiro Kurosaki

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  1. Takeshi Inoue
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T.K. contributed to conceptualization of the article. All authors contributed to writing and editing of the manuscript.

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Correspondence to Tomohiro Kurosaki.

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Glossary

Affinity maturation

A process, as a result of somatic hypermutation (SHM) and B cell selection in the germinal centre (GC), by which B cells increase their affinity and avidity for the antigens.

Age-associated B cells

(ABCs). A subset of B cells expressing CD11c and the transcription factor T-bet, and lacking CD21 in mice. ABCs are shown to increase during both ageing and autoimmunity.

Antibody feedback

An immunological phenomenon in which antibodies can either enhance or suppress the antigen-specific B cell responses.

Atypical memory B cells

A subset of memory B cells expressing inhibitory molecules and lacking surface CD21 and CD27 in humans. Atypical memory B cells often develop in individuals with chronic infection or autoimmune disease, and are characterized by their reduced effector function.

B1 and B2 B cells

B cell populations that differ in development, tissue localization and function. B2 B cells are the major and conventional B cell population abundant in the spleen, lymph nodes and peripheral blood, which participate in the germinal centre (GC) reaction to produce high-affinity antibodies. B1 B cells are enriched in the peritoneal and pleural cavities, which recognize self-components and common bacterial antigens, and are the major source of natural IgM antibodies.

T follicular helper cells

(TFH cells). A subset of activated CD4+ T cells expressing the chemokine receptor CXCR5 and the transcription factor BCL-6. TFH cells provide help to B cells for activation, germinal centre (GC) formation and affinity maturation.

Somatic hypermutation

(SHM). A process by which B cells accumulate point mutations in their immunoglobulin genes, thus diversifying the specificity and affinity of their B cell receptors (BCRs) for the antigens.

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Inoue, T., Kurosaki, T. Memory B cells. Nat Rev Immunol 24, 5–17 (2024). https://doi.org/10.1038/s41577-023-00897-3

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