TY - JOUR
T1 - 1,25-Dihyroxyvitamin D 3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region
AU - Kang, Seong Wook
AU - Kim, Sang Hyun
AU - Lee, Naeun
AU - Lee, Won Woo
AU - Hwang, Kyung A.
AU - Shin, Min Sun
AU - Lee, Seung Hyun
AU - Kim, Wan Uk
AU - Kang, Insoo
PY - 2012/6/1
Y1 - 2012/6/1
N2 - 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) 2VD 3] affects the functions of immune cells including T cells. 1,25(OH) 2VD 3 binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH) 2VD 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) 2VD 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) 2VD 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) 2VD 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) 2VD 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.
AB - 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) 2VD 3] affects the functions of immune cells including T cells. 1,25(OH) 2VD 3 binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH) 2VD 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) 2VD 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) 2VD 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) 2VD 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) 2VD 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.
UR - http://www.scopus.com/inward/record.url?scp=84862093116&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1101211
DO - 10.4049/jimmunol.1101211
M3 - Article
C2 - 22529297
AN - SCOPUS:84862093116
SN - 0022-1767
VL - 188
SP - 5276
EP - 5282
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -