Abstract
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-γ+CD4 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 in vivo. 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.
Highlights
Aminoacyl-tRNA synthetases are enzymes related to aminoacylation that cognate amino acid to a specific-tRNA
To investigate whether tRNA synthetase (TRS) stimulated the expression of these maturation-related cell surface molecules on dendritic cell (DC), bone marrowderived DCs were incubated for 20 h in the presence or absence of TRS and the expression of the cell surface molecules was assessed by cytofluorometric analysis
As TRS is found in the sera of autoimmune patients, it is of interest to investigate its non-translation functions, especially, its cytokine-like activity in the regulation of inflammatory responses and the immune modulatory functions of DCs, which shape Ag-specific T cell immunity
Summary
Aminoacyl-tRNA synthetases (aaRSs) are enzymes related to aminoacylation that cognate amino acid to a specific-tRNA. In addition to the essential function catalyzing aminoacylation function, some of the aaRSs are secreted into the extracellular environment, similar to cytokines, in specific conditions, and have various non-canonical functions. These include the control of transcription, translation [1] and RNA processing [2], as well as anti-viral immunity [3, 4], angiogenesis [1] tumorigenesis [5], metastasis [6], apoptosis, and immune response [6,7,8] including pro-inflammatory effect [9, 10]. The effect of TRS on immunity involving dendritic cells (DCs) and DC-mediated T cell response remains unknown
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