title: 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region.
abstract: FOXP3-positive regulatory T (Treg) cells are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4(+) T cells (induced Treg [iTreg] cells) by TCR triggering, IL-2, and TGF-β or retinoic acid. 1,25-Dihyroxyvitamin D(3) [1,25(OH)(2)VD(3)] affects the functions of immune cells including T cells. 1,25(OH)(2)VD(3) binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH)(2)VD(3) can promote FOXP3 expression in CD4(+) T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)(2)VD(3) is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)(2)VD(3)-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. In this study, we demonstrated the presence of VDREs in the intronic conserved noncoding sequence region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)(2)VD(3). Additionally, VD-iTreg cells suppressed the proliferation of target CD4(+) T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)(2)VD(3) can affect human immune responses by regulating FOXP3 expression in CD4(+) T cells through direct VDR binding to the FOXP3 gene, which is essential for inhibitory function of VD-iTreg cells.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Seong Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Naeun
authors.initials: N
authors.lastname: Lee
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.forename: Kyung-A
authors.initials: KA
authors.lastname: Hwang
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Shin
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
authors.forename: Insoo
authors.initials: I
authors.lastname: Kang
mesh_terms: D000328:Adult; D001483:Base Sequence; D001665:Binding Sites / Q000276:immunology; D002117:Calcitriol / Q000502:physiology*; D017124:Conserved Sequence / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D018167:Receptors, Calcitriol / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D030181:Vitamin D Response Element / Q000235:genetics*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018167:Receptors, Calcitriol; D002117:Calcitriol