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 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
88 Citations (Scopus)


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.

Original languageEnglish
JournalNature Immunology
Issue number1
Pages (from-to)62-74
Number of pages13
Publication statusPublished - 01.2022

Research Areas and Centers

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

DFG Research Classification Scheme

  • 204-05 Immunology

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