Toll-like receptor 7 agonist imiquimod prevents the progression of SLE in MRL/lpr mice via inhibiting the differentiation of T follicular helper cells
Toll-like receptor 7 agonist imiquimod prevents the progression of SLE in MRL/lpr mice via inhibiting the differentiation of T follicular helper cells
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Toll 样受体 7 激动剂咪喹莫特通过抑制滤泡辅助 T 细胞的分化来预防 MRL/lpr 小鼠 SLE 的进展
DOI：
10.1016/j.intimp.2020.106239
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发表时间：
2020-03-01
影响因子：
5.6
通讯作者：
Su, Chunxia
中科院分区：
文献类型：
--
作者：
Duan, Xiangguo;Shen, Chunxiu;Su, Chunxia
先前的研究最近表明，TLR7能够诱导CD4(+) T细胞无反应性，这与其在先天免疫细胞中发挥的作用相反。因此，TLR7配体可作为诱导自身免疫性疾病中CD4(+)T细胞“耐受”的一种方式。滤泡辅助 T (Tfh) 细胞被证明是 CD4(+)T 细胞的一个子集，可帮助 B 细胞产生抗体。然而，Tfh 细胞的异常活性是其作为系统性红斑狼疮 (SLE) 的主要致病因素的功能。然而，TLR7在Tfh细胞中的作用尚不清楚。我们的研究旨在确定 TLR7 对 SLE 小鼠模型（MRL/lpr 小鼠）中 Tfh 细胞的影响。我们惊讶地发现，用 TLR7 激动剂咪喹莫特治疗后，Tfh 细胞和生发中心 (GC) B 细胞的频率显着降低。咪喹莫特还显着降低 Tfh 细胞中诱导共刺激分子 (ICOS) 和程序性死亡 1 (PD-1) 的表达，并减少 IL-21 的分泌。此外，咪喹莫特显着降低CD4+T细胞中多种转录因子的mRNA表达，包括Bcl-6、c-Maf、Batf3、Nfatc2和Stat3，并增强Prdm1和Stat56的表达。咪喹莫特还通过抑制血清中抗 dsDNA 抗体和抗核抗体 (ANA) 的分泌，改善 MRL/lpr 小鼠的 SLE 进展。我们的研究结果表明，TLR7 在体内和离体抑制 Tfh 细胞的发育，这依赖于除 Bcl-6 之外的许多转录因子。我们的结果表明，TLR7 激动剂有潜力用于抑制 SLE 期间的 Tfh 细胞反应。
Previous research has recently indicated that TLR7 is able to induce CD4(+) T cell anergy, which is the opposite of the role it plays in innate immune cells. Therefore, TLR7 ligands may be used as a manner in which to induce CD4(+) T cells "tolerance" in autoimmune diseases. T follicular helper (Tfh) cells were demonstrated to be a subset of CD4(+)T cells that help B cells produce antibodies. The abnormal activity of Tfh cells, though, is their function as a primary pathogenic factor in systemic lupus erythematosus (SLE). However, the role of TLR7 in Tfh cells is not clear. Our study was aimed at determining the influence of TLR7 on Tfh cells in a murine model of SLE (MRL/lpr mice). We were surprised to find that the frequency of Tfh cells and germinal center (GC) B cells was significantly reduced after treatment with the TLR7 agonist imiquimod. Imiquimod also significantly reduced the expression of inducible costimulatory molecule (ICOS) and programmed death 1(PD-1) in Tfh cells and decreased IL-21 secretion. Moreover, imiquimod significantly reduced the mRNA expression of several transcription factors, including Bcl-6, c-Maf, Batf3, Nfatc2 and Stat3, and enhanced the expression of Prdm1 and Stat56 in CD4(+)T cells. Imiquimod also ameliorated the progression of SLE in MRL/lpr mice by inhibiting anti-dsDNA antibodies and antinuclear antibody (ANA) secretion in the serum. Our findings indicated that TLR7 inhibited the development of Tfh cells both in vivo and ex vivo, which depended on many transcription factors aside from Bcl-6. Our results demonstrated that a TLR7 agonist has the potential to be used to inhibit Tfh cell responses during SLE.