Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells

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; Paul Lavender; Claudia Kemper; Giovanna Lombardi; Nehal N. Mehta; Nichola Cooper; Michail S. Lionakis; Arian Laurence; Majid Kazemian; Behdad Afzali

doi:10.1038/s41590-021-01080-3

Autocrine vitamin D signaling switches off pro-inflammatory programs of T_H1 cells

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 JohnPaul Lavender, Claudia Kemper, Giovanna Lombardi, Nehal N. Mehta, Nichola Cooper, Michail S. Lionakis, Arian Laurence, Majid Kazemian^*, Behdad Afzali^*

^*Corresponding author for this work

Institute of Systemic Inflamation Research

88 Citations (Scopus)

Abstract

The molecular mechanisms governing orderly shutdown and retraction of CD4⁺ type 1 helper T (T_H1) cell responses remain poorly understood. Here we show that complement triggers contraction of T_H1 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⁺ T_H1 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 T_H1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

Original language	English
Journal	Nature Immunology
Volume	23
Issue number	1
Pages (from-to)	62-74
Number of pages	13
ISSN	1529-2908
DOIs	https://doi.org/10.1038/s41590-021-01080-3
Publication status	Published - 01.2022

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

2.21-05 Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41590-021-01080-3

Cite this

Chauss, D., Freiwald, T., McGregor, R., Yan, B., Wang, L., Nova-Lamperti, E., Kumar, D., Zhang, Z., Teague, H., West, E. E., Vannella, K. M., Ramos-Benitez, M. J., Bibby, J., Kelly, A., Malik, A., Freeman, A. F., Schwartz, D. M., Portilla, D., Chertow, D. S., ... Afzali, B. (2022). Autocrine vitamin D signaling switches off pro-inflammatory programs of T_H1 cells. Nature Immunology, 23(1), 62-74. https://doi.org/10.1038/s41590-021-01080-3

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title = "Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2022",

month = jan,

doi = "10.1038/s41590-021-01080-3",

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Chauss, D, Freiwald, T, McGregor, R, Yan, B, Wang, L, Nova-Lamperti, E, Kumar, D, Zhang, Z, Teague, H, West, EE, Vannella, KM, Ramos-Benitez, MJ, Bibby, J, Kelly, A, Malik, A, Freeman, AF, Schwartz, DM, Portilla, D, Chertow, DS, John, S, Lavender, P, Kemper, C, Lombardi, G, Mehta, NN, Cooper, N, Lionakis, MS, Laurence, A, Kazemian, M & Afzali, B 2022, 'Autocrine vitamin D signaling switches off pro-inflammatory programs of T_H1 cells', Nature Immunology, vol. 23, no. 1, pp. 62-74. https://doi.org/10.1038/s41590-021-01080-3

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T1 - Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells

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

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.

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