All-Trans Retinoic Acid Induces CD4+CD25+FOXP3+ Regulatory T Cells by Increasing FOXP3 Demethylation in Systemic Sclerosis CD4+ T Cells.

Abstract

BACKGROUND:

Retinoic acid (RA) is an active metabolite of vitamin A and has been reported to improve the clinical symptoms of patients with systemic sclerosis (SSc). However, the mechanism of RA in the prevention of SSc remains unclear. Regulatory T cells (Tregs) are a subpopulation of T cells with immunosuppressive activity. The quantitative and functional defects of Tregs may mediate the immune dysfunction in SSc. The addition of all-trans retinoic acid (ATRA) to human naïve CD4+ cells could promote the maturation of Tregs and increase the stable expression of Foxp3. In this study, we explored the role of RA on Tregs in SSc CD4+ T cells and its possible epigenetic mechanisms, so as to further understand the mechanisms of RA on SSc.

METHODS:

CD4+ T cells were isolated from peripheral blood of SSc and treated with or without ATRA and/or transforming growth factor-β (TGF-β). The percentage of CD4+CD25+FOXP3+ Tregs was counted by flow cytometry. FOXP3 mRNA and protein levels were measured by quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. Bisulfite sequencing was performed to determine the methylation status of the FOXP3 proximal promoter sequences.

RESULTS:

The expression of Tregs and FOXP3 in CD4+ T cells from patients with SSc increased in response to ATRA. Moreover, combined stimulation with ATRA and TGF-β resulted in the enhancement of these effects. Further studies revealed that stimulation with ATRA increased the expression of FOXP3 in SSc CD4+ T cells by downregulating FOXP3 promoter methylation levels.

CONCLUSIONS:

ATRA acts as an inducer of Treg response in SSc CD4+ T cells via demethylation of the FOXP3 promoter and activation of FOXP3 expression. This may be one of the molecular mechanisms for ATRA, and therefore, RA can be used for the treatment of SSc.

• Authors: Xiaohong Sun, Yangfan Xiao, Zhuotong Zeng, Yaqian Shi, Bingsi Tang, Hai Long, Takuro Kanekura, Jiucun Wang, Haijing Wu, Ming Zhao, Qianjin Lu, Rong Xiao
• Journal: Journal of immunology research (J Immunol Res) Vol. 2018 Pg. 8658156 ( 2018) ISSN: 2314-7156 [Electronic] Egypt
• PMID: 29854846 (Publication Type: Journal Article)

Chemical References

• CD4 Antigens
• FOXP3 protein, human
• Forkhead Transcription Factors
• Interleukin-2 Receptor alpha Subunit
• Transforming Growth Factor beta
• Tretinoin

Topics

• CD4 Antigens (metabolism)
• Cell Differentiation
• Cells, Cultured
• DNA Methylation
• Demethylation
• Epigenesis, Genetic
• Flow Cytometry
• Forkhead Transcription Factors (genetics, metabolism)
• Humans
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Scleroderma, Systemic (drug therapy, immunology)
• T-Lymphocytes, Regulatory (immunology)
• Transforming Growth Factor beta (metabolism)
• Tretinoin (pharmacology, therapeutic use)
• Up-Regulation