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

Nat Immunol. 2022 Jan;23(1):62-74. doi: 10.1038/s41590-021-01080-3. Epub 2021 Nov 11.

Authors

Daniel Chauss^#¹, Tilo Freiwald^#^{1

2}, Reuben McGregor^#^{1

3}, Bingyu Yan^#⁴, Luopin Wang^#⁵, Estefania Nova-Lamperti⁶, Dhaneshwar Kumar^{1

5}, Zonghao Zhang⁷, Heather Teague⁸, Erin E West⁹, Kevin M Vannella^{10

11}, Marcos J Ramos-Benitez^{10

11}, Jack Bibby⁹, Audrey Kelly¹², Amna Malik¹³, Alexandra F Freeman¹⁴, Daniella M Schwartz¹⁵, Didier Portilla^{1

16}, Daniel S Chertow^{10

11}, Susan John¹², Paul Lavender¹², Claudia Kemper^{9

17}, Giovanna Lombardi¹², Nehal N Mehta⁸, Nichola Cooper¹³, Michail S Lionakis¹⁸, Arian Laurence¹⁹, Majid Kazemian^{20

21}, Behdad Afzali²²

Affiliations

¹ Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA.
² Medic Clinic III, Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt, Germany.
³ Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
⁴ Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
⁵ Department of Computer Science, Purdue University, West Lafayette, IN, USA.
⁶ Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepcion, Concepcion, Chile.
⁷ Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN, USA.
⁸ Laboratory of Inflammation & Cardiometabolic Diseases, Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA.
⁹ Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA.
¹⁰ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
¹¹ Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
¹² Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
¹³ Department of Medicine, Imperial College London, London, UK.
¹⁴ Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
¹⁵ Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
¹⁶ Division of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁷ Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
¹⁸ Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
¹⁹ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
²⁰ Department of Biochemistry, Purdue University, West Lafayette, IN, USA. [email protected].
²¹ Department of Computer Science, Purdue University, West Lafayette, IN, USA. [email protected].
²² Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
Basic-Leucine Zipper Transcription Factors / metabolism
Bronchoalveolar Lavage Fluid / cytology
COVID-19 / immunology
COVID-19 / pathology
Complement C3a / immunology
Complement C3b / immunology
Humans
Interferon-gamma / immunology*
Interleukin-10 / immunology*
JNK Mitogen-Activated Protein Kinases / metabolism
Lymphocyte Activation / immunology
Receptors, Calcitriol / metabolism
Respiratory Distress Syndrome / immunology
Respiratory Distress Syndrome / pathology
Respiratory Distress Syndrome / virology
SARS-CoV-2 / immunology*
STAT3 Transcription Factor / metabolism
Signal Transduction / immunology
Th1 Cells / immunology*
Transcription, Genetic / genetics
Vitamin D / metabolism*

Substances

BACH2 protein, human
Basic-Leucine Zipper Transcription Factors
IFNG protein, human
IL10 protein, human
Receptors, Calcitriol
STAT3 Transcription Factor
STAT3 protein, human
VDR protein, human
Interleukin-10
Vitamin D
Complement C3a
Complement C3b
Interferon-gamma
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
CYP27B1 protein, human
JNK Mitogen-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding