title: 1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter.
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.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schedel
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jia
authors.affiliation: University Children's Hospital Regensburg (KUNO), Department of Pediatric Pneumology and Allergy, Steinmetzstrasse 1-3, 93049 Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse, 30625 Hannover, Germany.
authors.forename: Sven
authors.identifier: http://orcid.org/0000-0003-3604-3187
authors.initials: S
authors.lastname: Michel
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Domenico
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Fangkun
authors.initials: F
authors.lastname: Ning
authors.affiliation: Division of Biostatistics and Bioinformatics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Strand
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Han
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Meiqin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lucas
authors.affiliation: Department of Pediatrics, University Children's Hospital, Technical University, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Vogelberg
authors.affiliation: University Children's Hospital Regensburg (KUNO), Department of Pediatric Pneumology and Allergy, Steinmetzstrasse 1-3, 93049 Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse, 30625 Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.|Center for Genes, Environment and Health, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.|Department of Immunology and Microbiology, University of Colorado AMC, 13001 E 17th Place, Aurora, Colorado 80045, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Connor
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002117:Calcitriol / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010047:Ovalbumin; D020641:Polymorphism, Single Nucleotide; D011284:Pregnenolone / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000485:Allergens; D018793:Interleukin-13; D018167:Receptors, Calcitriol; D011284:Pregnenolone; D007371:Interferon-gamma; D010047:Ovalbumin; D002786:Cholesterol Side-Chain Cleavage Enzyme; D002117:Calcitriol