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Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet

Nature Medicine volume 23, pages 601–610 (2017)Cite this article

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Abstract

Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (TFH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-TFH cells, leading to PDL1-mediated suppression of TFH cell motility, alteration of TFH cell differentiation, reduced TFH abundance and suppression of the proatherogenic TFH response. Our findings reveal a previously unsuspected role for MZB cells in controlling the TFH–germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.

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Figure 1: MZB cells limit the development of atherosclerosis.
Figure 2: MZB cells limit development of atherosclerosis through inhibition of the TFH response.
Figure 3: An HCD activates a homeostatic and anti-inflammatory program in MZB cells.
Figure 4: ATF3 expression in MZB cells controls TFH accumulation in response to an HCD and is required for the atheroprotective effect of MZB cells.
Figure 5: MZB cells limit TFH motility and control the proatherogenic TFH–GC response through upregulation of PDL1.
Figure 6: MZB cells control the TFH program during atherosclerosis.

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Acknowledgements

We acknowledge A. Petrunkina, E. Perez, C. Bowman, S. McCallum, J. Markovic Djuric and N. Savinykh in the Phenotyping Hub of the Department of Medicine (University of Cambridge) for their help in flow cytometry and sorting and M. Ozsvar Kozma (Medical University of Vienna) for help in antibody measurements. We also acknowledge M. Ma for support during library preparation for RNA–seq. This work was supported by BHF grant no. PG/15/76/31756, BHF grant no. PG/13/73/30466, ERC grant no. 2891164 and EC FP7 VIA grant no. HEALTH-F4-2013-603131 to Z.M. and by SAF2013-45543-R from the Spanish Ministry of Economy and Competitiveness (MINECO) to J.L.d.l.P. M.N. was first supported by a Sara Borrell grant (CD09/00452) from the Instituto Nacional de Salud Carlos III (Spain) and then by a 2-year BHF Project Grant. M.N. has also received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 608765. We acknowledge measurements of lipids in blood by K. Burling. The Wellcome Trust supported the Cambridge Mouse Biochemistry Laboratory.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK

    Meritxell Nus, Andrew P Sage, Yuning Lu, Leanne Masters, Stephen Newland, Juliette Raffort, Damiënne Marcus, Alison Finigan, Lauren Kitt, Nichola Figg & Ziad Mallat

  2. Metabolic Research Laboratories, University of Cambridge and MRC Metabolic Diseases Unit, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, UK

    Brian Y H Lam & Giles S H Yeo

  3. Institut Necker–Enfants Malades, INSERM U1151, CNRS UMR 8253, Sorbonne, Paris Cité, Université Paris Descartes, Paris, France

    Sandra Weller

  4. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Dimitrios Tsiantoulas & Christoph J Binder

  5. Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria

    Dimitrios Tsiantoulas & Christoph J Binder

  6. Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany

    Reinhold Schirmbeck

  7. Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany

    Manfred Kneilling

  8. Department of Dermatology, Eberhard Karls University, Tübingen, Germany

    Manfred Kneilling

  9. Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

    José Luis de la Pompa

  10. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain

    José Luis de la Pompa

  11. INSERM, Unit 970, Paris Cardiovascular Research Center, Paris, France

    Ziad Mallat

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  1. Meritxell Nus
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Contributions

M.N. and Z.M. conceived the study; M.N. designed, performed and analyzed the results of experiments; A.P.S. performed experiments and provided advice on design and discussion; Y.L. performed time-lapse microscopy experiments; S.N., J.R. and D.M. performed experiments related to the atherosclerosis studies; L.M., A.F., L.K. and N.F. helped significantly with flow cytometry, animal work and immunohistochemistry, respectively; S.W. provided and analyzed human spleens crucial to this study; D.T. performed and interpreted blood antibody measurements; R.S., M.K. and J.L.d.l.P. developed and provided mice and cells crucial for the paper; B.Y.H.L. performed bioinformatic analyses on the RNA–seq data; G.S.H.Y. supervised and interpreted the RNA–seq analyses; C.J.B. advised on antibody measurement and contributed significantly to the intellectual content of the paper; Z.M. supervised the entire study; and M.N. and Z.M. prepared the manuscript. All authors contributed to and approved the final manuscript.

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Correspondence to Ziad Mallat.

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Nus, M., Sage, A., Lu, Y. et al. Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet. Nat Med 23, 601–610 (2017). https://doi.org/10.1038/nm.4315

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