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

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

doi:10.1038/ncomms10213

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.

Highlights

Effector CD8 þ T cells convert from IFN-g þ (Tc1) to IL-13 þ (Tc2) cells in the presence of IL-4
We previously demonstrated that in the presence of IL-4, CD8 þ T cells convert from IFN-g CD8 þ effector T cells to pathogenic IL-13 producers, triggering the full spectrum of lung allergic responses[4,27]
1,25D3 has almost no effect on the vitamin D receptor (VDR) recruitment in CD8 þ T cells after IL-2 stimulation alone. These results suggest that VDR binding to the Cyp11a1 promoter acts as a transcriptional repressor since the reduction in VDR recruitment to its promoter leads to increased CYP11A1 gene and protein expression (Fig. 2c,e) and elevated pregnenolone levels (Fig. 2f)

Summary

Introduction

Effector CD8 þ T cells convert from IFN-g þ (Tc1) to IL-13 þ (Tc2) cells in the presence of IL-4. An association between lower levels of vitamin D and increased asthma severity, reduced lung function and poor asthma control has been suggested[19,20,21,22,23,24,25] It is unclear if vitamin D supplementation impacts the disease as seen in a recent trial in asthmatics[26] but a potential mechanism of action remains unknown. Together with antigen receptor signalling of differentiated CD8 þ T cells, CYP11A1 activation was essential for increased IL-13 and decreased IFN-g production[4,27] These data linked for the first time steroidogenesis in CD8 þ T cells, a non-classical steroidogenic tissue, to a pro-allergic differentiation pathway

Methods

Findings

Conclusion