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Nat Commun. 2016 Jan 11;7:10213. doi: 10.1038/ncomms10213.

1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter.

Author information

1
Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
2
University Children's Hospital Regensburg (KUNO), Department of Pediatric Pneumology and Allergy, Steinmetzstrasse 1-3, 93049 Regensburg, Germany.
3
Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse, 30625 Hannover, Germany.
4
Division of Biostatistics and Bioinformatics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
5
Department of Pediatrics, University Children's Hospital, Technical University, Fetscherstraße 74, 01307 Dresden, Germany.
6
Center for Genes, Environment and Health, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
7
Department of Immunology and Microbiology, University of Colorado AMC, 13001 E 17th Place, Aurora, Colorado 80045, USA.

Abstract

Effector CD8(+) T cells convert from IFN-γ(+) (Tc1) to IL-13(+) (Tc2) cells in the presence of IL-4. Underlying regulatory mechanisms are not fully defined. Here, we show that addition of 1,25D3, the active form of vitamin D3, during CD8(+) T-cell differentiation prevents IL-4-induced conversion to IL-13-producers. Transfer of 1,25D3-treated CD8(+) T cells into sensitized and challenged CD8(+)-deficient recipients fails to restore development of lung allergic responses. 1,25D3 alters vitamin D receptor (VDR) recruitment to the Cyp11a1 promoter in vitro and in vivo in the presence of IL-4. As a result, protein levels and enzymatic activity of CYP11A1, a steroidogenic enzyme regulating CD8(+) T-cell conversion, are decreased. An epistatic effect between CYP11A1 and VDR polymorphisms may contribute to the predisposition to childhood asthma. These data identify a role for 1,25D3 in the molecular programming of CD8(+) T-cell conversion to an IL-13-secreting phenotype through regulation of steroidogenesis, potentially governing asthma susceptibility.

PMID:
26750596
PMCID:
PMC4712703
DOI:
10.1038/ncomms10213
[Indexed for MEDLINE]
Free PMC Article

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