TY - JOUR
T1 - Autocrine vitamin D signaling switches off pro-inflammatory programs of T
AU - Chauss, Daniel
AU - Freiwald, Tilo
AU - McGregor, Reuben
AU - Yan, Bingyu
AU - Wang, Luopin
AU - Nova-Lamperti, Estefania
AU - Kumar, Dhaneshwar
AU - Zhang, Zonghao
AU - Teague, Heather
AU - West, Erin E.
AU - Vannella, Kevin M.
AU - Ramos-Benitez, Marcos J.
AU - Bibby, Jack
AU - Kelly, Audrey
AU - Malik, Amna
AU - Freeman, Alexandra F.
AU - Schwartz, Daniella M.
AU - Portilla, Didier
AU - Chertow, Daniel S.
AU - John, Susan
AU - Lavender, Paul
AU - Kemper, Claudia
AU - Lombardi, Giovanna
AU - Mehta, Nehal N.
AU - Cooper, Nichola
AU - Lionakis, Michail S.
AU - Laurence, Arian
AU - Kazemian, Majid
AU - Afzali, Behdad
N1 - 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.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118857169&partnerID=8YFLogxK
U2 - 10.1038/s41590-021-01080-3
DO - 10.1038/s41590-021-01080-3
M3 - Article
AN - SCOPUS:85118857169
SN - 1529-2916
VL - 23
SP - 62
EP - 74
JO - Nature Immunology
JF - Nature Immunology
IS - 1
ER -