1,25-Dihyroxyvitamin D 3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region

Seong Wook Kang, Sang Hyun Kim, Naeun Lee, Won Woo Lee, Kyung A. Hwang, Min Sun Shin, Seung Hyun Lee, Wan Uk Kim, Insoo Kang

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

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) 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.

Original languageEnglish
Pages (from-to)5276-5282
Number of pages7
JournalJournal of Immunology
Volume188
Issue number11
DOIs
StatePublished - 1 Jun 2012

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