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

Schedel, Michaela ; Jia, Yi ; Michel, Sven ; Takeda, Katsuyuki ; Domenico, Joanne ; Joetham, Anthony ; Ning, Fangkun ; Strand, Matthew ; Han, Junyan ; Wang, Meiqin ; Lucas, Joseph J ; Vogelberg, Christian ; Kabesch, Michael ; O'Connor, Brian P ; Gelfand, Erwin W

Nature communications, 2016-01, Vol.7 (1), p.10213-10213, Article 10213 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter
Autor: Schedel, Michaela ; Jia, Yi ; Michel, Sven ; Takeda, Katsuyuki ; Domenico, Joanne ; Joetham, Anthony ; Ning, Fangkun ; Strand, Matthew ; Han, Junyan ; Wang, Meiqin ; Lucas, Joseph J ; Vogelberg, Christian ; Kabesch, Michael ; O'Connor, Brian P ; Gelfand, Erwin W
Assuntos: Adolescent ; Adoptive Transfer ; Allergens ; Animals ; Asthma ; Asthma - genetics ; Asthma - immunology ; Asthma - metabolism ; Calcitriol - immunology ; Calcitriol - metabolism ; Case-Control Studies ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Cell differentiation ; Child ; Children ; Cholesterol Side-Chain Cleavage Enzyme - genetics ; Cholesterol Side-Chain Cleavage Enzyme - immunology ; Cholesterol Side-Chain Cleavage Enzyme - metabolism ; Chromatin Immunoprecipitation ; Computer Simulation ; Conversion ; Differentiation (biology) ; Effector cells ; Enzymatic activity ; Enzyme-Linked Immunosorbent Assay ; Epistasis ; Flow Cytometry ; Genetic Predisposition to Disease ; Humans ; Hypersensitivity ; Immunoblotting ; Interferon-gamma - immunology ; Interferon-gamma - metabolism ; Interleukin 13 ; Interleukin 4 ; Interleukin-13 - immunology ; Interleukin-13 - metabolism ; Lung - immunology ; Lung - metabolism ; Lung - pathology ; Lungs ; Lymphocytes ; Lymphocytes T ; Mice ; Ovalbumin ; Phenotypes ; Polymorphism, Single Nucleotide ; Pregnenolone - metabolism ; Proteins ; Receptors, Calcitriol - genetics ; Receptors, Calcitriol - immunology ; Receptors, Calcitriol - metabolism ; Regulatory mechanisms (biology) ; Reverse Transcriptase Polymerase Chain Reaction ; Steroidogenesis ; T-Lymphocytes, Cytotoxic - immunology ; Vitamin D ; Vitamin D receptors ; Vitamin D3 ; γ-Interferon
É parte de: Nature communications, 2016-01, Vol.7 (1), p.10213-10213, Article 10213
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These authors contributed equally to this work.
Present address: Asia and Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, Shanghai 201203, China.
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

Schedel, Michaela ; Jia, Yi ; Michel, Sven ; Takeda, Katsuyuki ; Domenico, Joanne ; Joetham, Anthony ; Ning, Fangkun ; Strand, Matthew ; Han, Junyan ; Wang, Meiqin ; Lucas, Joseph J ; Vogelberg, Christian ; Kabesch, Michael ; O'Connor, Brian P ; Gelfand, Erwin W

England: Nature Publishing Group

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