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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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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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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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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DOI: https://doi.org/10.1038/nm.4315
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