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Autocrine vitamin D signaling switches off pro-inflammatory programs of T

Research output: Contribution to journalArticlepeer-review

Daniel Chauss, Tilo Freiwald, Reuben McGregor, Bingyu Yan, Luopin Wang, Estefania Nova-Lamperti, Dhaneshwar Kumar, Zonghao Zhang, Heather Teague, Erin E. West, Kevin M. Vannella, Marcos J. Ramos-Benitez, Jack Bibby, Audrey Kelly, Amna Malik, Alexandra F. Freeman, Daniella M. Schwartz, Didier Portilla, Daniel S. Chertow, Susan John & 9 more Paul Lavender, Claudia Kemper, Giovanna Lombardi, Nehal N. Mehta, Nichola Cooper, Michail S. Lionakis, Arian Laurence, Majid Kazemian, Behdad Afzali

Original languageEnglish
Pages (from-to)62-74
Number of pages13
JournalNature Immunology
Volume23
Issue number1
Early online date11 Nov 2021
DOIs
Accepted/In press2021
E-pub ahead of print11 Nov 2021
PublishedJan 2022

Bibliographical note

Funding Information: The authors thank patients who contributed samples for this study. We acknowledge G. Denisov and the NIH HPC (Biowulf) for their efforts in maintaining essential bioinformatic programs. We thank Q. Zhu, N. Liu, D. Janssens and S. Henikoff for critical discussions related to CUT&RUN experimentation and data analysis. This work was supported by the Wellcome Trust (grant 097261/Z/11/Z to B.A.), the Crohn’s and Colitis Foundation of America (grant CCFA no. 3765 — CCFA genetics initiative to A.L.), British Heart Foundation (grant RG/13/12/30395 to G.L.), the National Institute of General Medical Sciences (R35GM138283 to M.K.), the Showalter Trust (research award to M.K.), German Research Foundation (DFG scholarship to T.F.; FR 3851/2-1), the NIDDK (DK12262401A1 to D.P.) and the National Agency of Research and Development of Chile (grant PAI79170073 to E.N.L.). Research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. This research was supported (in part) by the Intramural Research Programs of the NIDDK (project no. ZIA/DK075149 to B.A), the National Heart, Lung and Blood Institute (project nos. ZIA/Hl006223 to C.K. and ZIA/HL006193 to N.M.), the NIAID (project no. ZIA/AI001175 to M.S.L.) of the NIH. D.C. is supported by an NIH Office of Dietary Supplements research scholar award. Publisher Copyright: © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

King's Authors

Abstract

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

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