Journal
EPIGENETICS
Volume 15, Issue 12, Pages 1275-1288Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15592294.2020.1767373
Keywords
MDSC; epigenetics; DNA methylation; immunosuppression
Funding
- Qatar Biomedical Research Institute, Qatar Foundation [VR04]
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Myeloid cells, including antigen-presenting cells (APCs) and myeloid-derived suppressor cells (MDSCs) play opposing roles to orchestrate innate and adaptive immune responses during physiological and pathological conditions. We investigated the role of DNA methylation in regulating the transcription of inhibitory/suppressive molecules in myeloid suppressive cells (identified as CD33(+)HLA-DR-) in comparison to APCs. We selected a number of immune checkpoints (ICs), IC ligands, and immunosuppressive molecules that have been implicated in MDSC function, including PD-L1, TIM-3, VISTA, galectin-9, TGF-beta, ARG1 and MMP9. We examined their mRNA expression levels, and investigated whether DNA methylation regulates their transcription in sorted myeloid cell subpopulations. We found that mRNA levels of PD-L1, TIM-3, TGF-beta, ARG1 and MMP9 in CD33(+)HLA-DR- cells were higher than APCs. However, VISTA and galectin-9 mRNA levels were relatively similar in both myeloid subpopulations. CpG islands in the promoter regions of TGF-beta 1, TIM-3 and ARG1 were highly unmethylated in CD33(+)HLA-DR(-)cells, compared with APCs, suggesting that DNA methylation is one of the key mechanisms, which regulate their expression. However, we did not find differences in the methylation status of PD-L1 and MMP9 between CD33(+)HLA-DR- and APCs, suggesting that their transcription could be regulated via other genetic and epigenetic mechanisms. The promoter methylation status of VISTA was relatively similar in both myeloid subpopulations. This study provides novel insights into the epigenetic mechanisms, which control the expression of inhibitory/suppressive molecules in circulating CD33(+)HLA-DR- cells in a steady-state condition, possibly to maintain immune tolerance and haemostasis.
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