Department of Life Science, College of Life Science and Biotechnology, Korea University, Seoul, South Korea.
Institute of Convergence Science, Korea University, Seoul, South Korea.
Front Immunol. 2020 Oct 14;11:571959. doi: 10.3389/fimmu.2020.571959. eCollection 2020.
Threonyl-tRNA synthetase (TRS) is an aminoacyl-tRNA synthetase that catalyzes the aminoacylation of tRNA by transferring threonine. In addition to an essential role in translation, TRS was extracellularly detected in autoimmune diseases and also exhibited pro-angiogenetic activity. TRS is reported to be secreted into the extracellular space when vascular endothelial cells encounter tumor necrosis factor-α. As T helper (Th) type 1 response and IFN-γ levels are associated with autoimmunity and angiogenesis, in this study, we investigated the effects of TRS on dendritic cell (DC) activation and CD4 T cell polarization. TRS-treated DCs exhibited up-regulated expression of activation-related cell-surface molecules, including CD40, CD80, CD86, and MHC class II. Treatment of DCs with TRS resulted in a significant increase of IL-12 production. TRS triggered nuclear translocation of the NF-κB p65 subunit along with the degradation of IκB proteins and the phosphorylation of MAPKs in DCs. Additionally, MAPK inhibitors markedly recovered the degradation of IκB proteins and the increased IL-12 production in TRS-treated DCs, suggesting the involvement of MAPKs as the upstream regulators of NF-κB in TRS-induced DC maturation and activation. Importantly, TRS-stimulated DCs significantly increased the populations of IFN-γCD4 T cells, and the levels of IFN-γ when co-cultured with CD4 T cells. The addition of a neutralizing anti-IL-12 mAb to the cell cultures of TRS-treated DCs and CD4 T cells resulted in decreased IFN-γ production, indicating that TRS-stimulated DCs may enhance the Th1 response through DC-derived IL-12. Injection of OT-II mice with OVA-pulsed, TRS-treated DCs also enhanced Ag-specific Th1 responses . Importantly, injection with TRS-treated DC exhibited increased populations of IFN-γ-CD4 and -CD8 T cells as well as secretion level of IFN-γ, resulting in viral clearance and increased survival periods in mice infected with influenza A virus (IAV), as the Th1 response is associated with the enhanced cellular immunity, including anti-viral activity. Taken together, these results indicate that TRS promotes the maturation and activation of DCs, DC-mediated Th1 responses, and anti-viral effect on IAV infection.
苏氨酰-tRNA 合成酶（TRS）是一种氨酰-tRNA 合成酶，可通过转移苏氨酸催化 tRNA 的氨酰化。除了在翻译中发挥重要作用外，TRS 还在外周自身免疫性疾病中被检测到，并表现出促血管生成活性。当血管内皮细胞遇到肿瘤坏死因子-α时，据报道 TRS 会分泌到细胞外空间。由于辅助性 T 细胞（Th）1 型反应和 IFN-γ水平与自身免疫和血管生成有关，因此在这项研究中，我们研究了 TRS 对树突状细胞（DC）激活和 CD4 T 细胞极化的影响。TRS 处理的 DC 表现出激活相关细胞表面分子的上调表达，包括 CD40、CD80、CD86 和 MHC Ⅱ类。TRS 处理的 DC 导致 IL-12 产生显著增加。TRS 触发 NF-κB p65 亚基在 DC 中的核易位，同时 IκB 蛋白降解和 MAPK 的磷酸化。此外，MAPK 抑制剂明显恢复了 TRS 处理的 DC 中 IκB 蛋白的降解和增加的 IL-12 产生，表明 MAPK 作为 TRS 诱导的 DC 成熟和激活中 NF-κB 的上游调节剂参与其中。重要的是，TRS 刺激的 DC 显著增加了 IFN-γCD4 T 细胞的群体，并且当与 CD4 T 细胞共培养时 IFN-γ的水平增加。向 TRS 处理的 DC 和 CD4 T 细胞的细胞培养物中添加中和抗 IL-12 mAb 会导致 IFN-γ产生减少，表明 TRS 刺激的 DC 可能通过 DC 衍生的 IL-12 增强 Th1 反应。用 OVA 脉冲的 TRS 处理的 DC 注射到 OT-II 小鼠中也增强了 Ag 特异性 Th1 反应。重要的是，注射 TRS 处理的 DC 增加了 IFN-γ-CD4 和 -CD8 T 细胞的群体以及 IFN-γ的分泌水平，导致流感病毒 A（IAV）感染的清除和存活期延长，因为 Th1 反应与增强的细胞免疫有关，包括抗病毒活性。总之，这些结果表明 TRS 促进了 DC 的成熟和激活、DC 介导的 Th1 反应以及对 IAV 感染的抗病毒作用。
