Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, 750004 Yinchuan, PR China; Department of Laboratory Surgery, General Hospital of Ningxia Medical University, 750004 Yinchuan, PR China.
School of Basic Medical Sciences , Ningxia Medical University, 750004 Yinchuan, PR China.
Int Immunopharmacol. 2020 Mar;80:106239. doi: 10.1016/j.intimp.2020.106239. Epub 2020 Jan 30.
Previous research has recently indicated that TLR7 is able to induce CD4T 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 CD4T cells "tolerance" in autoimmune diseases. T follicular helper (Tfh) cells were demonstrated to be a subset of CD4T 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 Stat5b in CD4T 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.
先前的研究最近表明，TLR7 能够诱导 CD4T 细胞失能，这与它在先天免疫细胞中所起的作用相反。因此，TLR7 配体可用作在自身免疫性疾病中诱导 CD4T 细胞“耐受”的一种方式。滤泡辅助性 T（Tfh）细胞被证明是帮助 B 细胞产生抗体的 CD4T 细胞亚群之一。然而，Tfh 细胞的异常活性是系统性红斑狼疮（SLE）中主要的致病因素之一。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 在 SLE 小鼠模型（MRL/lpr 小鼠）中对 Tfh 细胞的影响。我们惊讶地发现，TLR7 激动剂咪喹莫特治疗后 Tfh 细胞和生发中心（GC）B 细胞的频率显著降低。咪喹莫特还显著降低了 Tfh 细胞中诱导共刺激分子（ICOS）和程序性死亡 1（PD-1）的表达，并减少了 IL-21 的分泌。此外，咪喹莫特显著降低了包括 Bcl-6、c-Maf、Batf3、Nfatc2 和 Stat3 在内的几种转录因子的 mRNA 表达，并增强了 CD4T 细胞中 Prdm1 和 Stat5b 的表达。咪喹莫特还通过抑制抗 dsDNA 抗体和血清中抗核抗体（ANA）的分泌，改善了 MRL/lpr 小鼠的 SLE 进展。我们的发现表明，TLR7 抑制了体内和体外 Tfh 细胞的发育，这取决于除了 Bcl-6 之外的许多转录因子。我们的结果表明，TLR7 激动剂有可能用于抑制 SLE 期间的 Tfh 细胞反应。
