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B cell signaling in context

Nature Immunology volume 20, pages 963–969 (2019)Cite this article

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Abstract

Over the past several decades, B cell antigen receptor (BCR)-induced signaling pathways have been described in extraordinary molecular detail, mainly from studies of B cell responses to antigens in vitro. BCR signaling has been shown to govern the initiation of transcriptional programs associated with B cell activation and fate decisions, as well as the BCR-dependent processing of antigen and presentation of antigen to T cells. However, although the potential of the BCR to orchestrate B cell behavior was known, there was no clear appreciation of the context in which B cells signal in secondary lymphoid organs in vivo or how that context influences signaling. In this Review, we describe the current view of the cellular consequences of BCR signaling and advances in the understanding of B cell signaling in context in vivo.

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Fig. 1: Antigen-driven antibody responses.
Fig. 2: B cell spreading and contraction in response to membrane associated antigens.
Fig. 3: B cell immune responses to antigen in lymph nodes.

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References

  1. Tangye, S. G. & Tarlinton, D. M. Memory B cells: effectors of long-lived immune responses. Eur. J. Immunol. 39, 2065–2075 (2009).

    Article  CAS  Google Scholar 

  2. De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).

    Article  Google Scholar 

  3. Shinnakasu, R. & Kurosaki, T. Regulation of memory B and plasma cell differentiation. Curr. Opin. Immunol. 45, 126–131 (2017).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Goodnow, C. C., Vinuesa, C. G., Randall, K. L., Mackay, F. & Brink, R. Control systems and decision making for antibody production. Nat. Immunol. 11, 681–688 (2010).

    Article  CAS  Google Scholar 

  6. Harwood, N. E. & Batista, F. D. Early events in B cell activation. Annu. Rev. Immunol. 28, 185–210 (2010).

    Article  CAS  Google Scholar 

  7. Kurosaki, T., Shinohara, H. & Baba, Y. B cell signaling and fate decision. Annu. Rev. Immunol. 28, 21–55 (2010).

    Article  CAS  Google Scholar 

  8. Chaturvedi, A., Martz, R., Dorward, D., Waisberg, M. & Pierce, S. K. Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments. Nat. Immunol. 12, 1119–1126 (2011).

    Article  CAS  Google Scholar 

  9. Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nat. Rev. Immunol. 9, 15–27 (2009).

    Article  CAS  Google Scholar 

  10. Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).

    Article  CAS  Google Scholar 

  11. Kräutler, N. J. et al. Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J. Exp. Med. 214, 1259–1267 (2017).

    Article  Google Scholar 

  12. Tangye, S. G., Brink, R., Goodnow, C. C. & Phan, T. G. SnapShot: interactions between B cells and T cells. Cell 162, 926–926.e921 (2015).

    Article  CAS  Google Scholar 

  13. Rawlings, D. J., Schwartz, M. A., Jackson, S. W. & Meyer-Bahlburg, A. Integration of B cell responses through Toll-like receptors and antigen receptors. Nat. Rev. Immunol. 12, 282–294 (2012).

    Article  CAS  Google Scholar 

  14. Ruprecht, C. R. & Lanzavecchia, A. Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol. 36, 810–816 (2006).

    Article  CAS  Google Scholar 

  15. Fleire, S. J. et al. B cell ligand discrimination through a spreading and contraction response. Science 312, 738–741 (2006). These authors (ref. 15) first described the spreading and contraction response of B cells to antigen presented on a membrane surface and related this response to B cell antigen discrimination.

    Article  CAS  Google Scholar 

  16. Gonzalez, S. F. et al. Trafficking of B cell antigen in lymph nodes. Annu. Rev. Immunol. 29, 215–233 (2011).

    Article  CAS  Google Scholar 

  17. Pierce, S. K. & Liu, W. The tipping points in the initiation of B cell signalling: how small changes make big differences. Nat. Rev. Immunol. 10, 767–777 (2010).

    Article  CAS  Google Scholar 

  18. Bannard, O. & Cyster, J. G. Germinal centers: programmed for affinity maturation and antibody diversification. Curr. Opin. Immunol. 45, 21–30 (2017). This highly insightful, comprehensive short review (ref. 18) discusses affinity maturation mechanisms in germinal centers.

    Article  CAS  Google Scholar 

  19. Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010). This manuscript (ref. 19) reveals germinal center dynamics in vivo using multiphoton microscopy.

    Article  CAS  Google Scholar 

  20. Shulman, Z. et al. T follicular helper cell dynamics in germinal centers. Science 341, 673–677 (2013).

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Pereira, J. P., Kelly, L. M., Xu, Y. & Cyster, J. G. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009).

    Article  CAS  Google Scholar 

  23. Coffey, F., Alabyev, B. & Manser, T. Initial clonal expansion of germinal center B cells takes place at the perimeter of follicles. Immunity 30, 599–609 (2009).

    Article  CAS  Google Scholar 

  24. Gitlin, A. D., Shulman, Z. & Nussenzweig, M. C. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014).

    Article  CAS  Google Scholar 

  25. Caro-Maldonado, A. et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 192, 3626–3636 (2014).

    Article  CAS  Google Scholar 

  26. Doughty, C. A. et al. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107, 4458–4465 (2006).

    Article  CAS  Google Scholar 

  27. Jellusova, J. et al. Gsk3 is a metabolic checkpoint regulator in B cells. Nat. Immunol. 18, 303–312 (2017).

    Article  CAS  Google Scholar 

  28. Boothby, M. & Rickert, R. C. Metabolic regulation of the immune humoral response. Immunity 46, 743–755 (2017).

    Article  CAS  Google Scholar 

  29. Tsui, C. et al. Protein kinase C-β dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis. Immunity 48, 1144–1159.e1145 (2018).

    Article  CAS  Google Scholar 

  30. Benhamron, S., Pattanayak, S. P., Berger, M. & Tirosh, B. mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion. Mol. Cell. Biol. 35, 153–166 (2015).

    Article  Google Scholar 

  31. 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  Google Scholar 

  32. Akkaya, M. et al. Second signals rescue B cells from activation-induced mitochondrial dysfunction and death. Nat. Immunol. 19, 871–884 (2018). Here, the authors (ref. 32) describe the activation-induced cell death phenomenon in B cells with links to mitochondrial fitness and metabolic remodeling. B cells stimulated via antigen rapidly increase energy production, but this initial activation must be sustained by the receipt of secondary signals through either TLRs or cognate B cell–T cell interactions. If a BCR-activated B cell receives neither of these signals, then the initial activation fades and the B cell dies due to dysregulated calcium homeostasis and mitochondrial dysfunction.

    Article  CAS  Google Scholar 

  33. Turner, J. S., Marthi, M., Benet, Z. L. & Grigorova, I. Transiently antigen-primed B cells return to naive-like state in absence of T-cell help. Nat. Commun. 8, 15072 (2017).

    Article  Google Scholar 

  34. Akkaya, M. et al. Toll-like receptor 9 antagonizes antibody affinity maturation. Nat. Immunol. 19, 255–266 (2018). This manuscript (ref. 34) describes how receipt of additional signals through TLR9 influences the fate of antigen-induced B cells. In summary, TLR9 signals block multiple elements of the internalization and processing of BCR-bound antigens, which leads to weaker B cell–T cell interactions but on the other hand drives rapid proliferation and extrafollicular differentiation.

    Article  CAS  Google Scholar 

  35. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669–1672 (2006).

    Article  CAS  Google Scholar 

  36. Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  Google Scholar 

  37. Tipton, C. M., Hom, J. R., Fucile, C. F., Rosenberg, A. F. & Sanz, I. Understanding B-cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B-cell immunomics approach. Immunol. Rev. 284, 120–131 (2018).

    Article  CAS  Google Scholar 

  38. DeFranco, A. L., Rookhuizen, D. C. & Hou, B. Contribution of Toll-like receptor signaling to germinal center antibody responses. Immunol. Rev. 247, 64–72 (2012).

    Article  Google Scholar 

  39. 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  Google Scholar 

  40. Liu, W., Meckel, T., Tolar, P., Sohn, H. W. & Pierce, S. K. Antigen affinity discrimination is an intrinsic function of the B cell receptor. J. Exp. Med. 207, 1095–1111 (2010).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  42. Benson, M. J., Erickson, L. D., Gleeson, M. W. & Noelle, R. J. Affinity of antigen encounter and other early B-cell signals determine B-cell fate. Curr. Opin. Immunol. 19, 275–280 (2007).

    Article  CAS  Google Scholar 

  43. Tolar, P. Cytoskeletal control of B cell responses to antigens. Nat. Rev. Immunol. 17, 621–634 (2017).

    Article  CAS  Google Scholar 

  44. Natkanski, E. et al. B cells use mechanical energy to discriminate antigen affinities. Science 340, 1587–1590 (2013). These authors (ref. 44) provided the first evidence that B cells utilize mechanical energy to discriminate antigen affinities through myosin IIa activity.

    Article  CAS  Google Scholar 

  45. Liu, B., Chen, W. & Zhu, C. Molecular force spectroscopy on cells. Annu. Rev. Phys. Chem. 66, 427–451 (2015).

    Article  CAS  Google Scholar 

  46. Wan, Z. et al. The activation of IgM- or isotype-switched IgG- and IgE-BCR exhibits distinct mechanical force sensitivity and threshold. eLife 4, e06925 (2015).

    Article  Google Scholar 

  47. Liu, W. et al. The scaffolding protein synapse-associated protein 97 is required for enhanced signaling through isotype-switched IgG memory B cell receptors. Sci. Signal. 5, ra54 (2012).

    PubMed  PubMed Central  Google Scholar 

  48. Engels, N. et al. The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module. Nat. Commun. 5, 5456 (2014).

    Article  CAS  Google Scholar 

  49. Spillane, K. M. & Tolar, P. B cell antigen extraction is regulated by physical properties of antigen-presenting cells. J. Cell Biol. 216, 217–230 (2017).

    Article  CAS  Google Scholar 

  50. Bufi, N. et al. Human primary immune cells exhibit distinct mechanical properties that are modified by inflammation. Biophys. J. 108, 2181–2190 (2015).

    Article  CAS  Google Scholar 

  51. Muñoz-Fernández, R. et al. Contractile activity of human follicular dendritic cells. Immunol. Cell Biol. 92, 851–859 (2014).

    Article  Google Scholar 

  52. Sacquin, A., Gador, M. & Fazilleau, N. The strength of BCR signaling shapes terminal development of follicular helper T cells in mice. Eur. J. Immunol. 47, 1295–1304 (2017).

    Article  CAS  Google Scholar 

  53. 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.e704 (2018).

    Article  CAS  Google Scholar 

  54. Khalil, A. M., Cambier, J. C. & Shlomchik, M. J. B cell receptor signal transduction in the GC is short-circuited by high phosphatase activity. Science 336, 1178–1181 (2012).

    Article  CAS  Google Scholar 

  55. Nowosad, C. R., Spillane, K. M. & Tolar, P. Germinal center B cells recognize antigen through a specialized immune synapse architecture. Nat. Immunol. 17, 870–877 (2016).

    Article  CAS  Google Scholar 

  56. 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.e315 (2018).

    Article  CAS  Google Scholar 

  57. Kwak, K. et al. Intrinsic properties of human germinal center B cells set antigen affinity thresholds. Sci. Immunol. 3, eaau6598 (2018).These authors (ref. 57) provided evidence for the structural basis of affinity discrimination in GC B cells. GC B cells form unconventional actin- and ezrin-rich pod-like structures after being activated by membrane-bound antigen, through which GC B cells test the affinity of their BCRs.

    Article  Google Scholar 

  58. Mueller, J., Matloubian, M. & Zikherman, J. Cutting edge: an in vivo reporter reveals active B cell receptor signaling in the germinal center. J. Immunol. 194, 2993–2997 (2015).

    Article  CAS  Google Scholar 

  59. Carrasco, Y. R. & Batista, F. D. B-cell activation by membrane-bound antigens is facilitated by the interaction of VLA-4 with VCAM-1. EMBO J. 25, 889–899 (2006).

    Article  CAS  Google Scholar 

  60. Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).

    Article  CAS  Google Scholar 

  61. Schroeder, K. M., Agazio, A. & Torres, R. M. Immunological tolerance as a barrier to protective HIV humoral immunity. Curr. Opin. Immunol. 47, 26–34 (2017).

    Article  CAS  Google Scholar 

  62. Cancro, M. P. & Kearney, J. F. B cell positive selection: road map to the primary repertoire? J. Immunol. 173, 15–19 (2004).

    Article  CAS  Google Scholar 

  63. Chen, Y. et al. Microbial symbionts regulate the primary Ig repertoire. J. Exp. Med. 215, 1397–1415 (2018).

    Article  CAS  Google Scholar 

  64. Mouquet, H., Warncke, M., Scheid, J. F., Seaman, M. S. & Nussenzweig, M. C. Enhanced HIV-1 neutralization by antibody heteroligation. Proc. Natl Acad. Sci. USA 109, 875–880 (2012).

    Article  CAS  Google Scholar 

  65. Verkoczy, L. et al. Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc. Natl Acad. Sci. USA 107, 181–186 (2010).

    Article  CAS  Google Scholar 

  66. Doyle-Cooper, C. et al. Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10. J. Immunol. 191, 3186–3191 (2013).

    Article  CAS  Google Scholar 

  67. 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 e136 (2018).

    Article  CAS  Google Scholar 

  68. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    Article  CAS  Google Scholar 

  69. Zikherman, J., Parameswaran, R. & Weiss, A. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489, 160–164 (2012).

    Article  CAS  Google Scholar 

  70. Übelhart, R. et al. Responsiveness of B cells is regulated by the hinge region of IgD. Nat. Immunol. 16, 534–543 (2015).

    Article  Google Scholar 

  71. Sabouri, Z. et al. IgD attenuates the IgM-induced anergy response in transitional and mature B cells. Nat. Commun. 7, 13381 (2016).

    Article  CAS  Google Scholar 

  72. Noviski, M. et al. IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate. eLife 7, e35074 (2018).

    Article  Google Scholar 

  73. Han, S., Zheng, B., Dal Porto, J. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J. Exp. Med. 182, 1635–1644 (1995).

    Article  CAS  Google Scholar 

  74. Pulendran, B., Kannourakis, G., Nouri, S., Smith, K. G. & Nossal, G. J. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 375, 331–334 (1995).

    Article  CAS  Google Scholar 

  75. Shokat, K. M. & Goodnow, C. C. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375, 334–338 (1995).

    Article  CAS  Google Scholar 

  76. Chan, T. D. et al. Elimination of germinal-center-derived self-reactive B cells is governed by the location and concentration of self-antigen. Immunity 37, 893–904 (2012).

    Article  CAS  Google Scholar 

  77. Burnett, D. L. et al. Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination. Science 360, 223–226 (2018). These authors (ref. 77) describe how a small subset of autoreactive anergic B cells can mutate away from self reactivity to escape deletion and then participate in affinity maturation, a process called ‘clonal redemption’. Remarkably, the initial mutation away from self-reactivity positions these clones on a unique, rapid trajectory toward affinity maturation.

    Article  CAS  Google Scholar 

  78. 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  Google Scholar 

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Acknowledgements

Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. The authors thank R. Kissinger (of that institution) for expert preparation of the illustrations presented here.

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

    Kihyuck Kwak, Munir Akkaya & Susan K. Pierce

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Kwak, K., Akkaya, M. & Pierce, S.K. B cell signaling in context. Nat Immunol 20, 963–969 (2019). https://doi.org/10.1038/s41590-019-0427-9

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