CoChat
Sign Up
Cited by 47T-cell and B-cell ImmunologyImmunotherapy and Immune ResponsesChemokine receptors and signaling

Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift

Open access
Zhang, Yang, Garcia-Ibanez, Laura, Ulbricht, Carolin, Lok, Laurence S. C., Pike, Jeremy A., Mueller-Winkler, Jennifer, Dennison, Thomas W., Ferdinand, John R. +13 more·2022·Nature Communications
DOI 10.1038/s41467-022-29978-yPMC PMC9072412
Open this paper in CoChat — free accountOpen PDF

Abstract

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (B EM) and find that many B EM cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, B EM cells may exit the lymph node to enter distant tissues, while some B EM cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of B EM cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific B EM cells and transport of antigen back to GC may support affinity maturation to antigenic drift.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-022-29978-y

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • T cells, B cells, and some neutrophils may leave the lymph node.

    “By contrast, T cells, B cells, and some neutrophils may leave the lymph node (93, 95, 96).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [96]

    The Discussion states that some memory B cells leave the lymph node and appear in other organs; the Results describe a possible route through efferent lymph. The paper does not establish that T cells or neutrophils leave the lymph node, so it supports only the B-cell part of the cited sentence. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • T cells exit the lymph node through paracortical sinuses, whereas B cells exit through the SCS and medullary sinuses.

    “T cells exit through paracortical sinuses, whereas B cells exit through the SCS and medullary sinuses (93, 96).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [96]

    The Results section (“Appearance of memory-like B cells entering the SCS guided by S1PR”; page unavailable) links emigration of GC-derived memory-like B cells to the SCS. The Discussion says lymphocytes are thought to leave via the medulla and efferent lymph, but does not specifically establish medullary-sinus exit for B cells. Our copy does not describe T-cell exit through paracortical sinuses. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 72

  1. [1]Zhang Y Garcia-Ibanez L Toellner K-M Regulation of germinal centre B cell differentiation Immunol. Rev. 2016 270 8 19 10.1111/imr.12396 26864101 PMC4755139 · DOI
  2. [2]Yoshida T Memory B and memory plasma cells Immunol. Rev. 2010 237 117 139 10.1111/j.1600-065X.2010.00938.x 20727033 · DOI
  3. [3]Weisel FJ Zuccarino-Catania GV Chikina M Shlomchik MJ A temporal switch in the germinal center determines differential output of memory B and plasma cells Immunity 2016 44 116 130 10.1016/j.immuni.2015.12.004 26795247 PMC4724390 · DOI · Paper page
  4. [4]Zhang Y Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells J. Exp. Med. 2018 215 1227 1243 10.1084/jem.20160832 29549115 PMC5881458 · DOI
  5. [5]Laidlaw BJ The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells J. Exp. Med. 2017 214 639 649 10.1084/jem.20161461 28143955 PMC5339677 · DOI
  6. [6]Landsverk OJ Antibody-secreting plasma cells persist for decades in human intestine J. Exp. Med. 2017 214 309 317 10.1084/jem.20161590 28104812 PMC5294861 · DOI
  7. [7]Gitlin AD Independent roles of switching and hypermutation in the development and persistence of B lymphocyte memory Immunity 2016 44 769 781 10.1016/j.immuni.2016.01.011 26944202 PMC4838502 · DOI
  8. [8]Pape KA Cells with high-avidity germline-encoded antigen receptors produce persistent IgM(+) and transient IgG(+) memory B cells Immunity 2018 48 1135 1143 e1134 10.1016/j.immuni.2018.04.019 29884459 PMC6052797 · DOI
  9. [9]Shinnakasu R Regulated selection of germinal-center cells into the memory B cell compartment Nat. Immunol. 2016 17 861 869 10.1038/ni.3460 27158841 · DOI
  10. [10]Suan D CCR6 defines memory B cell precursors in mouse and human germinal centers, revealing light-zone location and predominant low antigen affinity Immunity 2017 47 1142 1153 e1144 10.1016/j.immuni.2017.11.022 29262350 · DOI
  11. [11]Viant C Antibody affinity shapes the choice between memory and germinal center B cell fates Cell 2020 183 1298 1311 e1211 10.1016/j.cell.2020.09.063 33125897 PMC7722471 · DOI · Paper page
  12. [12]Zinkernagel RM What if protective immunity is antigen-driven and not due to so-called “memory” B and T cells? Immunol. Rev. 2018 283 238 246 10.1111/imr.12648 29664570 · DOI
  13. [13]Ise W Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells Proc. Natl Acad. Sci. USA 2014 111 11792 11797 10.1073/pnas.1404671111 25071203 PMC4136626 · DOI
  14. [14]Jelcic I Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis Cell 2018 175 85 100 e123 10.1016/j.cell.2018.08.011 30173916 PMC6191934 · DOI
  15. [15]Toellner K-M Gulbranson-Judge A Taylor DR Sze DM-Y MacLennan ICM Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation J. Exp. Med. 1996 183 2303 2312 10.1084/jem.183.5.2303 8642339 PMC2192570 · DOI
  16. [16]Moran I Memory B cells are reactivated in subcapsular proliferative foci of lymph nodes Nat. Commun. 2018 9 3372 10.1038/s41467-018-05772-7 30135429 PMC6105623 · DOI
  17. [17]Mesin L Restricted clonality and limited germinal center reentry characterize memory B cell reactivation by boosting Cell 2020 180 92 106 e111 10.1016/j.cell.2019.11.032 31866068 PMC6958527 · DOI
  18. [18]Yi T Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses Immunity 2012 37 535 548 10.1016/j.immuni.2012.06.015 22999953 PMC3465460 · DOI
  19. [19]Moseman EA B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity Immunity 2012 36 415 426 10.1016/j.immuni.2012.01.013 22386268 PMC3359130 · DOI
  20. [20]Carrasco YR Batista FD B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node Immunity 2007 27 160 171 10.1016/j.immuni.2007.06.007 17658276 · DOI
  21. [22]Arnon TI GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood Science 2011 333 1898 1903 10.1126/science.1208248 21960637 PMC3267326 · DOI
  22. [23]Sonoda E B cell development under the condition of allelic inclusion Immunity 1997 6 225 233 10.1016/S1074-7613(00)80325-8 9075923 · DOI
  23. [24]Kallies A Plasma cell ontogeny defined by quantitative changes in blimp-1 expression J. Exp. Med 2004 200 967 977 10.1084/jem.20040973 15492122 PMC2211847 · DOI
  24. [25]Sakaue-Sawano A Visualizing spatiotemporal dynamics of multicellular cell-cycle progression Cell 2008 132 487 498 10.1016/j.cell.2007.12.033 18267078 · DOI
  25. [26]Stein H Immunohistologic analysis of the organization of normal lymphoid tissue and non-Hodgkin’s lymphomas J. Histochem. Cytochem. 1980 28 746 760 10.1177/28.8.7003001 7003001 · DOI
  26. [27]Liu, Y-J, Oldfield, S, MacLennan, ICM. Thymus-independent type 2 responses in lymph nodes. In: Advances in Experimental Medicine and Biology (eds Fossum S, Rolstad B). In Proc. of the Ninth International Conference on Lymphatic Tissues and Germinal Centres in Immune Reactions, August 10–14 1987 (Oslo, Norway edn. Plenum Press, 1988).
  27. [28]Aiba Y Preferential localization of IgG memory B cells adjacent to contracted germinal centers Proc. Natl Acad. Sci. USA 2010 107 12192 12197 10.1073/pnas.1005443107 20547847 PMC2901464 · DOI
  28. [29]Casola S Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting Proc. Natl Acad. Sci. USA 2006 103 7396 7401 10.1073/pnas.0602353103 16651521 PMC1464351 · DOI
  29. [30]Cascalho M Ma A Lee S Masat L Wabl M A quasi-monoclonal mouse Science 1996 272 1649 1652 10.1126/science.272.5268.1649 8658139 · DOI
  30. [31]Marshall JL Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts Eur. J. Immunol. 2011 41 3506 3512 10.1002/eji.201141762 21932446 · DOI
  31. [32]Muzumdar MD Tasic B Miyamichi K Li L Luo L A global double-fluorescent Cre reporter mouse Genesis 2007 45 593 605 10.1002/dvg.20335 17868096 · DOI · Paper page
  32. [33]Girard JP Moussion C Forster R HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes Nat. Rev. Immunol. 2012 12 762 773 10.1038/nri3298 23018291 · DOI · Paper page
  33. [34]Green JA Cyster JG S1PR2 links germinal center confinement and growth regulation Immunol. Rev. 2012 247 36 51 10.1111/j.1600-065X.2012.01114.x 22500830 PMC3335345 · DOI
  34. [35]Stoler-Barak L B cell dissemination patterns during the germinal center reaction revealed by whole-organ imaging J. Exp. Med. 2019 216 2515 2530 10.1084/jem.20190789 31492809 PMC6829594 · DOI
  35. [36]Zhang Y Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node Elife 2016 5 e18156 10.7554/eLife.18156 27487469 PMC5017864 · DOI
  36. [37]Ulvmar MH The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes Nat. Immunol. 2014 15 623 630 10.1038/ni.2889 24813163 · DOI · Paper page
  37. [38]Kozai M Essential role of CCL21 in establishment of central self-tolerance in T cells J. Exp. Med. 2017 214 1925 1935 10.1084/jem.20161864 28611158 PMC5502431 · DOI
  38. [39]Huang HY Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis Proc. Natl Acad. Sci. USA 2018 115 E6826 E6835 29967180 PMC6055158
  39. [40]Reif K Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position Nature 2002 416 94 99 10.1038/416094a 11882900 · DOI
  40. [41]Okada T Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells PLoS Biol. 2005 3 e150 10.1371/journal.pbio.0030150 15857154 PMC1088276 · DOI
  41. [42]Okada T Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches J. Exp. Med. 2002 196 65 75 10.1084/jem.20020201 12093871 PMC2194009 · DOI
  42. [43]Phan TG Grigorova I Okada T Cyster JG Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells Nat. Immunol. 2007 8 992 1000 10.1038/ni1494 17660822 · DOI
  43. [44]Phan TG Green JA Gray EE Xu Y Cyster JG Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation Nat. Immunol. 2009 10 786 793 10.1038/ni.1745 19503106 PMC2776777 · DOI
  44. [45]Roco JA Class-switch recombination occurs infrequently in germinal centers Immunity 2019 51 337 350 e337 10.1016/j.immuni.2019.07.001 31375460 PMC6914312 · DOI
  45. [46]Jalkanen S Salmi M Lymphatic endothelial cells of the lymph node Nat. Rev. Immunol. 2020 20 566 578 10.1038/s41577-020-0281-x 32094869 · DOI · Paper page
  46. [47]Ngo VN Tang HL Cyster JG Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells J. Exp. Med. 1998 188 181 191 10.1084/jem.188.1.181 9653094 PMC2525549 · DOI
  47. [48]Cremasco V B cell homeostasis and follicle confines are governed by fibroblastic reticular cells Nat. Immunol. 2014 15 973 981 10.1038/ni.2965 25151489 PMC4205585 · DOI
  48. [49]Werth K Expression of ACKR4 demarcates the “peri-marginal sinus,” a specialized vascular compartment of the splenic red pulp Cell Rep. 2021 36 109346 10.1016/j.celrep.2021.109346 34260918 · DOI
  49. [50]Gatto D Paus D Basten A Mackay CR Brink R Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses Immunity 2009 31 259 269 10.1016/j.immuni.2009.06.016 19615922 · DOI
  50. [51]Kelly LM Pereira JP Yi T Xu Y Cyster JG EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues J. Immunol. 2011 187 3026 3032 10.4049/jimmunol.1101262 21844396 PMC3169736 · DOI
  51. [52]Rodda LB Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity Immunity 2018 48 1014 1028 e1016 10.1016/j.immuni.2018.04.006 29752062 PMC5971117 · DOI
  52. [53]Batista FD Harwood NE The who, how and where of antigen presentation to B cells Nat. Rev. Immunol. 2009 9 15 27 10.1038/nri2454 19079135 · DOI
  53. [54]Cuevas JM Geller R Garijo R Lopez-Aldeguer J Sanjuan R Extremely high mutation rate of HIV-1 in vivo PLoS Biol. 2015 13 e1002251 10.1371/journal.pbio.1002251 26375597 PMC4574155 · DOI · Paper page
  54. [55]Vega VB Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003 BMC Infect. Dis. 2004 4 32 10.1186/1471-2334-4-32 15347429 PMC517714 · DOI
  55. [56]Schoofs T Broad and potent neutralizing antibodies recognize the silent face of the HIV envelope Immunity 2019 50 1513 1529 e1519 10.1016/j.immuni.2019.04.014 31126879 PMC6591006 · DOI
  56. [57]Comerford I The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses Blood 2010 116 4130 4140 10.1182/blood-2010-01-264390 20562329 · DOI
  57. [58]Srinivas S Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus BMC Dev. Biol. 2001 1 4 10.1186/1471-213X-1-4 11299042 PMC31338 · DOI · Paper page
  58. [59]Forster R CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs Cell 1999 99 23 33 10.1016/S0092-8674(00)80059-8 10520991 · DOI
  59. [61]Madisen L A robust and high-throughput Cre reporting and characterization system for the whole mouse brain Nat. Neurosci. 2010 13 133 140 10.1038/nn.2467 20023653 PMC2840225 · DOI · Paper page
  60. [62]Zhang Y Garcia-Ibanez L Brown G Toellner KM Detecting gene expression in lymphoid microenvironments by laser microdissection and quantitative RT-PCR Methods Mol. Biol. 2017 1623 21 36 10.1007/978-1-4939-7095-7_2 28589344 · DOI
  61. [63]Zhang Y Germinal center B cells govern their own fate via antibody feedback J. Exp. Med. 2013 210 457 464 10.1084/jem.20120150 23420879 PMC3600904 · DOI
  62. [64]Schindelin J Fiji: an open-source platform for biological-image analysis Nat. Methods 2012 9 676 682 10.1038/nmeth.2019 22743772 PMC3855844 · DOI · Paper page
  63. [65]Hulsen T de Vlieg J Alkema W BioVenn—a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams BMC Genom. 2008 9 488 10.1186/1471-2164-9-488 PMC2584113 18925949 · DOI
  64. [66]Clatworthy MR Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes Nat. Med. 2014 20 1458 1463 10.1038/nm.3709 25384086 PMC4283039 · DOI
  65. [67]Tinevez JY TrackMate: an open and extensible platform for single-particle tracking Methods 2017 115 80 90 10.1016/j.ymeth.2016.09.016 27713081 · DOI
  66. [68]Jaqaman K Robust single-particle tracking in live-cell time-lapse sequences Nat. Methods 2008 5 695 702 10.1038/nmeth.1237 18641657 PMC2747604 · DOI
  67. [69]Zhang, Y, et al. Recycling of memory B cell between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift. github.com/JeremyPike/SCS-cell-tracking10.5281/zenodo.6351432, (2022). PMC9072412 35513371
  68. [70]Berg S ilastik: interactive machine learning for (bio)image analysis Nat. Methods 2019 16 1226 1232 10.1038/s41592-019-0582-9 31570887 · DOI
  69. [71]Mank M A genetically encoded calcium indicator for chronic in vivo two-photon imaging Nat. Methods 2008 5 805 811 10.1038/nmeth.1243 19160515 PMC7618336 · DOI · Paper page
  70. [72]Rickert RC Roes J Rajewsky K B lymphocyte-specific, Cre-mediated mutagenesis in mice Nucleic Acids Res. 1997 25 1317 1318 10.1093/nar/25.6.1317 9092650 PMC146582 · DOI
  71. [73]Hauser AE Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns Immunity 2007 26 655 667 10.1016/j.immuni.2007.04.008 17509908 · DOI
  72. [74]Rakhymzhan A Synergistic strategy for multicolor two-photon microscopy: application to the analysis of germinal center reactions in vivo Sci. Rep. 2017 7 7101 10.1038/s41598-017-07165-0 28769068 PMC5540998 · DOI

Cited by

Sorted by citations

Authors
Zhang, Y., Garcia-Ibanez, L., Ulbricht, C., Lok, L. S. C., Pike, J. A., Mueller-Winkler, J., Dennison, T. W., Ferdinand, J. R., Burnett, C. J. M., Yam-Puc, J. C., Zhang, L., Alfaro, R. M., Takahama, Y., Ohigashi, I., Brown, G., Kurosaki, T., Tybulewicz, V. L. J., Rot, A., Hauser, A. E., Clatworthy, M. R., & Toellner, K.-M.
Affiliations
  • University of Birmingham (GB)
  • Humboldt-Universität zu Berlin (DE)
  • MRC Laboratory of Molecular Biology (GB)
  • University of Nottingham (GB)
  • The Francis Crick Institute (GB)
  • National Institutes of Health (US)
  • Institute of Advanced Medical Sciences, Tokushima University (JP)
  • Instituto Politécnico Nacional (MX)
  • RIKEN Center for Integrative Medical Sciences (JP)
  • Queen Mary University of London (GB)
Corresponding author
Toellner, Kai-Michael
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-05-05
Volume
13
Issue
1
Pages
2460-2460
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-29978-y
PMC
PMC9072412
OpenAlex
W4229013463
Cited by
47
References
1
Citations by year
2026: 10 · 2025: 8 · 2024: 12 · 2023: 11 · 2022: 6
FWCI
3.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (publishedVersion, cc-by)
  • University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
  • The Francis Crick Institute (cc-by)
Funders
  • RCUK | Biotechnology and Biological Sciences Research Council (BB/S003800/1, BB/M025292/1)
  • European Commission (DECIDE)
  • Wellcome Trust (104384/Z/14/Z, FC001194)
  • Cancer Research UK (FC001194)
  • Deutsche Forschungsgemeinschaft (TP17, C01, HA5354/10-1, TRR130)
  • RCUK | Medical Research Council (MR/N024907/1, MR/P001874/1)
  • DH | National Institute for Health Research (RP-2017-08-ST2-002)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
Keywords
memory B cells, germinal center, subcapsular sinus, B cell migration, affinity maturation, antigenic drift, antigenic variation, sphingosine-1-phosphate, antigen uptake, lymph nodes
MeSH terms
Antigenic Drift and Shift, Memory B Cells, B-Lymphocytes, Lymph Nodes, Germinal Center

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review