Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (TFH) cells in germinal centres. The rapid T–B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human TFH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. TFH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human TFH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T–B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T–B-cell synapse may be advantageous in the face of infection.

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  1. 1.

    & Neural and immunological synaptic relations. Science 298, 785–789 (2002)

  2. 2.

    & Norepinephrine: a messenger from the brain to the immune system. Immunol. Today 21, 539–542 (2000)

  3. 3.

    et al. Dopamine receptor expression on human T- and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study. J. Neuroimmunol. 132, 34–40 (2002)

  4. 4.

    , , , & Catecholamine content and in vitro catecholamine synthesis in peripheral human lymphocytes. J. Clin. Endocrinol. Metab. 81, 3553–3557 (1996)

  5. 5.

    , , , & Measurements of catecholamine-mediated apoptosis of immunocompetent cells by capillary electrophoresis. Electrophoresis 18, 1760–1766 (1997)

  6. 6.

    & Identification of catecholamines in the immune system by electrospray ionization mass spectrometry. Rapid Commun. Mass Spectrom. 12, 683–688 (1998)

  7. 7.

    , , & Acetylcholine-induced, calcium-dependent norepinephrine outflow from peripheral human lymphocytes. J. Neuroimmunol. 87, 82–87 (1998)

  8. 8.

    et al. Endogenous catecholamine synthesis, metabolism storage, and uptake in human peripheral blood mononuclear cells. Exp. Hematol. 27, 489–495 (1999)

  9. 9.

    et al. Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood 109, 632–642 (2007)

  10. 10.

    et al. Dopamine released by dendritic cells polarizes Th2 differentiation. Int. Immunol. 21, 645–654 (2009)

  11. 11.

    et al. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345, 1058–1062 (2014)

  12. 12.

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

  13. 13.

    , , & Follicular helper T cells. Annu. Rev. Immunol. 34, 335–368 (2016)

  14. 14.

    et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004)

  15. 15.

    , , & Dense-core granules: a specific hallmark of the neuronal/neurosecretory cell phenotype. J. Cell Sci. 117, 743–749 (2004)

  16. 16.

    et al. Sympathetic axons and nerve terminals: the protein composition of small and large dense-core and of a third type of vesicles. Neuroscience 37, 819–827 (1990)

  17. 17.

    et al. Molecular analysis of single B cells from T-cell-rich B-cell lymphoma shows the derivation of the tumor cells from mutating germinal center B cells and exemplifies means by which immunoglobulin genes are modified in germinal center B cells. Blood 93, 2679–2687 (1999)

  18. 18.

    et al. Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc. Natl Acad. Sci. USA 94, 9337–9342 (1997)

  19. 19.

    , & Tyrosine hydroxylase and regulation of dopamine synthesis. Arch. Biochem. Biophys. 508, 1–12 (2011)

  20. 20.

    et al. Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: implications for non-Hodgkin’s lymphoma. Proc. Natl Acad. Sci. USA 103, 13485–13490 (2006)

  21. 21.

    . & Pharmacology and biochemistry of haloperidol. Proc. R. Soc. Med. 69 (Suppl. 1), 3–8 (1976)

  22. 22.

    , & A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J. Exp. Med. 181, 1293–1301 (1995)

  23. 23.

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

  24. 24.

    et al. Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses. J. Immunol. 180, 5222–5234 (2008)

  25. 25.

    et al. Mechanism of antigen-driven selection in germinal centres. Nature 342, 929–931 (1989)

  26. 26.

    et al. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507, 118–123 (2014)

  27. 27.

    Overcoming the dichotomy of quantity and quality in antibody responses. J. Immunol. 193, 5414–5419 (2014)

  28. 28.

    et al. A theory of germinal center B cell selection, division, and exit. Cell Reports 2, 162–174 (2012)

  29. 29.

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

  30. 30.

    , , , & Effects of tissue age, presence of neurones and endothelin-3 on the ability of enteric neurone precursors to colonize recipient gut: implications for cell-based therapies. Neurogastroenterol. Motil. 22, 331–e86 (2010)

  31. 31.

    et al. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat. Immunol. 13, 491–498 (2012)

  32. 32.

    , & SIMPLE: a sequential immunoperoxidase labeling and erasing method. J. Histochem. Cytochem. 57, 899–905 (2009)

  33. 33.

    et al. The endoplasmic-sarcoplasmic reticulum of smooth muscle: immunocytochemistry of vas deferens fibers reveals specialized subcompartments differently equipped for the control of Ca2+ homeostasis. J. Cell Biol. 121, 1041–1051 (1993)

  34. 34.

    , , & Biochemical diagnosis of pheochromocytoma by simultaneous measurement of urinary excretion of epinephrine and norepinephrine. Clin. Chem. 38, 486–492 (1992)

  35. 35.

    , , & Catecholaminergic suppression of immunocompetent cells. Immunol. Today 19, 562–567 (1998)

  36. 36.

    et al. Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. Eur. J. Endocrinol. 154, 587–598 (2006)

  37. 37.

    . & Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods 25, 402–408 ( 2001)

  38. 38.

    , & Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014)

  39. 39.

    , , & in Current Protocols in Immunology (ed. et al.) Ch. 18, Unit 18.13 (Wiley, 2007)

  40. 40.

    , , & Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007)

  41. 41.

    , & Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014)

  42. 42.

    , & Recycling probability and dynamical properties of germinal center reactions. J. Theor. Biol. 210, 265–285 (2001)

  43. 43.

    & Immunology. Antigen feast or famine. Science 335, 408–409 (2012)

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We thank J. Meldolesi for electron microscopy analysis and P. Podini for technical assistance; M. Cook and E. Bartlett for reading the manuscript; R. Cairella for his contribution to preparing histological samples; A. Wilson, A.-M. Hatch, A. Lopez, E. Barry and T. Lambe for assistance with obtaining tonsil samples; and D. Yu for suggestions. We thank the Imaging and Cytometry Facility and the Biomolecular Research Facility at the John Curtin School of Medical Research for technical support. We acknowledge the contribution to this study made by the Oxford Centre for Histopathology Research and the Oxford Radcliffe Biobank, which are supported by the NIHR Oxford Biomedical Research Centre. C.G.V. is supported by fellowship, project, and program grants from the Australian National Health and Medical Research Council. The Wellcome Trust supports M.L.D. and S.V.; European Research Council grant AdG670930 supports M.L.D.; and D.S. Human Frontier Science Program (RGP0033/2015) supports M.M.H., M.L.D., and C.G.V.

Author information

Author notes

    • David Saliba
    •  & Maurilio Ponzoni

    These authors contributed equally to this work.


  1. Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia

    • Ilenia Papa
    • , Pablo F. Canete
    • , Paula Gonzalez-Figueroa
    • , Hayley A. McNamara
    • , Rebecca A. Sweet
    • , Ian A. Cockburn
    •  & Carola G. Vinuesa
  2. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK

    • David Saliba
    • , Salvatore Valvo
    •  & Michael L. Dustin
  3. Ateneo Vita-Salute, Department of Pathology, IRCCS Scientific Institute San Raffaele, Milan 20132, Italy

    • Maurilio Ponzoni
    •  & Claudio Doglioni
  4. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, New South Wales 2052, Australia

    • Sonia Bustamante
  5. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia

    • Michele Grimbaldeston
  6. OMNI-Biomarker Development, Genentech Inc., South San Francisco, California 94080, USA

    • Michele Grimbaldeston
  7. Imaging and Cytometry Facility, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia

    • Harpreet Vohra
  8. Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany

    • Michael Meyer-Hermann
  9. China-Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200085, China

    • Carola G. Vinuesa


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C.D. and C.G.V. contributed equally to this work. I.P. performed most of the experiments and analysed the data. P.C., P.G., and H.V. helped with the experiments. M.P. contributed to data analysis. D.S. and S.V. performed SLB experiments and contributed to interpretation together with M.L.D. S.B. performed GC/MS/MS experiments. M.M.-H. performed in silico modelling. H.M. performed two-photon experiments and contributed to data analysis together with I.C. M.G., M.L.D., M.M.-H., M.P., and R.A.S. provided intellectual input, expertise, and reading of the manuscript. I.P. and C.G.V. wrote the manuscript. C.G.V. supervised the project with D.C.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Carola G. Vinuesa.

Reviewer Information Nature thanks S. Crotty, J. Cyster, H. Qi, and the other anonymous reviewer(s) 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.

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    Supplementary Information

    This file contains Supplementary Figure 1 (the uncropped gels) and Supplementary Tables 1-2.


  1. 1.

    Live cell in vitro imaging

    FSK-treated TFH cells (blue), untreated TFH cells (green) and allogeneic GC B cells (red) were mixed together with a 1:2=T:B ratio and visualised for at least 30 minutes (See Methods for more details).

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