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

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, Michael Kabesch, Brian P. O’Connor and Erwin W. Gelfand ()
Additional contact information
Michaela Schedel: National Jewish Health
Yi Jia: National Jewish Health
Sven Michel: University Children’s Hospital Regensburg (KUNO)
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)
Brian P. O’Connor: National Jewish Health
Erwin W. Gelfand: National Jewish Health

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10213

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