Effects of CpG oligodeoxynucleotides on the differentiation of Treg/Th17 cells

•CpG 1826 can suppress the differentiation of iTreg cells via the reduced expression of Foxp3.•CpG 1826 can enhance the differentiation of Th17 cells through increasing levels of RORγt.•Vaccines together with CpG 1826 can significantly improve the survival of leukemic mice by alternate mechanisms. T...

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Published in:Molecular immunology 2021-04, Vol.132, p.199-208
Main Authors: Liu, Hailing, Ji, Yuqiang, Ma, Xiaorong, He, Aili, Zhao, Wanhong, Zhang, Pengyu, Gu, Liufang, Lei, Bo, Zhang, Yilin, Wang, Yueli, Zhang, Wanggang, Wang, Jin
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - drug effects
Cells, Cultured
CpG ODN
Cytokines - metabolism
Female
Forkhead Transcription Factors - metabolism
Leukemia
Mice
Mice, Inbred C57BL
Oligodeoxyribonucleotides - pharmacology
RNA, Messenger - metabolism
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - metabolism
Th17 cells
Th17 Cells - drug effects
Th17 Cells - metabolism
Transforming Growth Factor beta - metabolism
Treg cells
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Summary:•CpG 1826 can suppress the differentiation of iTreg cells via the reduced expression of Foxp3.•CpG 1826 can enhance the differentiation of Th17 cells through increasing levels of RORγt.•Vaccines together with CpG 1826 can significantly improve the survival of leukemic mice by alternate mechanisms. The balance between Th17 cells and T regulatory (Treg) cells has emerged as a prominent factor in regulating cancer development. However, the effect of CpG oligodeoxynucleotides (ODNs) on the differentiation of Treg/Th17 cells has not been well studied. We sought here to explore the function of CpG ODNs in the differentiation of Tregs and Th17 cells in vitro and in vivo. Mouse spleen cells were cultured with anti-CD3 monoclonal antibodies in vitro. Tregs and Th17 cell differentiation was induced by transforming growth factor (TGF)-β and interleukin (IL)-2, or TGF-β, IL-6, and IL-23, respectively. Then cells were treated with two CpG ODNs, CpG 1982, or CpG 1826. FBL-3-inoculated C57Bl/6 mice were treated with CpG 1826, tumor vaccine, or combination of CpG 1826 and tumor vaccine. After treatment, spleen cells and serum were isolated, and Tregs/Th17 cells were detected by flow cytometry. The expression of forkhead box P3 (Foxp3), retinoid-related orphan receptor gamma-t (RORγt), IL-10, and IL-17 mRNA was measured by real-time PCR, and protein levels were measured by Western blot and enzyme-linked immunosorbent assay. The frequency of Treg cells increased significantly (p < 0.05) in the FBL-3-inoculated leukemia mouse model compared with control mice, whereas the frequency of Th17 cells did not change. Median survival of mice after treatment with CpG 1826 and tumor vaccine was significantly prolonged compared with that of control mice (p < 0.05). The frequency of induced Treg cells decreased after treatment with CpG 1826, whereas the frequency of Th17 cells induced by cytokines in vitro and in the murine leukemia model increased following treatment with CpG 1826. Furthermore, after treatment with CpG 1826, the mRNA and protein levels of Foxp3 and IL-10 decreased significantly both in vitro and in vivo (p < 0.05), whereas those of RORγt and IL-17 increased significantly (p < 0.05). CpG 1826 may inhibit the differentiation of Treg cells induced by cytokines, promote the differentiation of Th17 cells in vitro and in murine leukemia models, and prolong the median survival of mice with leukemia.
ISSN:0161-5890
1872-9142
DOI:10.1016/j.molimm.2021.01.003