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Autocrine Vitamin D-signaling switches off pro-inflammatory programs of Th1 cells

The molecular mechanisms governing orderly shutdown and retraction of CD4(+) T helper (Th)1 responses remain poorly understood. Here, we show that complement triggers contraction of Th1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor (VDR) and the VitD-activating enzyme C...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612139/
https://www.ncbi.nlm.nih.gov/pubmed/34764490
http://dx.doi.org/10.1038/s41590-021-01080-3
Descripción
Sumario:The molecular mechanisms governing orderly shutdown and retraction of CD4(+) T helper (Th)1 responses remain poorly understood. Here, we show that complement triggers contraction of Th1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor (VDR) and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated transition from pro-inflammatory IFN-γ (+) Th1 cells to suppressive IL-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 VDR shaped the transcriptional response to VitD. Accordingly, VitD did not induce IL-10 in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4(+) T cells of COVID-19 patients were Th1-skewed and showed de-repression of genes down-regulated by VitD, either from lack of substrate (VitD deficiency) and/or abnormal regulation of this system.