TFH-derived dopamine accelerates productive synapses in germinal centres

  • Nature volume 547, pages 318323 (20 July 2017)
  • doi:10.1038/nature23013
  • Download Citation


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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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.

Extended data

Supplementary information

PDF files

  1. 1.

    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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