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

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Listed:
  • Michaela Schedel

    (National Jewish Health)

  • Yi Jia

    (National Jewish Health
    Present address: Asia and Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, Shanghai 201203, China.)

  • Sven Michel

    (University Children’s Hospital Regensburg (KUNO)
    Allergy and Neonatology, Hannover Medical School)

  • Katsuyuki Takeda

    (National Jewish Health)

  • Joanne Domenico

    (National Jewish Health)

  • Anthony Joetham

    (National Jewish Health)

  • Fangkun Ning

    (National Jewish Health)

  • Matthew Strand

    (National Jewish Health)

  • Junyan Han

    (National Jewish Health)

  • Meiqin Wang

    (National Jewish Health)

  • Joseph J. Lucas

    (National Jewish Health)

  • Christian Vogelberg

    (University Children’s Hospital, Technical University)

  • Michael Kabesch

    (University Children’s Hospital Regensburg (KUNO)
    Allergy and Neonatology, Hannover Medical School)

  • Brian P. O’Connor

    (National Jewish Health
    Center for Genes, Environment and Health, National Jewish Health
    University of Colorado AMC)

  • Erwin W. Gelfand

    (National Jewish Health)

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.

Suggested Citation

  • Michaela Schedel & Yi Jia & Sven Michel & Katsuyuki Takeda & Joanne Domenico & Anthony Joetham & Fangkun Ning & Matthew Strand & Junyan Han & Meiqin Wang & Joseph J. Lucas & Christian Vogelberg & Mich, 2016. "1,25D3 prevents CD8+Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10213
    DOI: 10.1038/ncomms10213
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