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

• Published in: Nature immunology Vol. 23; no. 1; pp. 62 - 74
• Main Authors: Chauss, Daniel, Freiwald, Tilo, McGregor, Reuben, Yan, Bingyu, Wang, Luopin, Nova-Lamperti, Estefania, Kumar, Dhaneshwar, Zhang, Zonghao, Teague, Heather, West, Erin E., Vannella, Kevin M., Ramos-Benitez, Marcos J., Bibby, Jack, Kelly, Audrey, Malik, Amna, Freeman, Alexandra F., Schwartz, Daniella M., Portilla, Didier, Chertow, Daniel S., John, Susan, Lavender, Paul, Kemper, Claudia, Lombardi, Giovanna, Mehta, Nehal N., Cooper, Nichola, Lionakis, Michail S., Laurence, Arian, Kazemian, Majid, Afzali, Behdad
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2022; Nature Publishing Group
• Subjects: 631/250/2152; 631/250/2501; 631/250/2502; 631/250/256; Autocrine signalling; Biomedical and Life Sciences; Biomedicine; Bronchus; c-Jun protein; CD4 antigen; Coronaviruses; COVID-19; Cytokines; Enhancers; Epigenetics; Gene silencing; Homeostasis; Immunology; Infectious Diseases; Inflammation; Interleukin 10; Lymphocytes; Lymphocytes T; Molecular modelling; Stat3 protein; Transcription factors; Vitamin D; Vitamin deficiency; γ-Interferon
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-021-01080-3

The molecular mechanisms governing orderly shutdown and retraction of CD4 + type 1 helper T (T H 1) cell responses remain poorly understood. Here we show that complement triggers contraction of T H 1 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 H 1 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 H 1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system. During homeostasis T H 1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this T H 1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.