Threonyl-tRNA Synthetase Promotes T Helper Type 1 Cell Responses by Inducing Dendritic Cell Maturation and IL-12 Production via an NF-κB Pathway

被引:15
作者
Jung, Hak-Jun [1 ]
Park, Su-Ho [1 ]
Cho, Kyung-Min [1 ]
Jung, Kwang Il [1 ]
Cho, Daeho [2 ]
Kim, Tae Sung [1 ]
机构
[1] Korea Univ, Dept Life Sci, Coll Life Sci & Biotechnol, Seoul, South Korea
[2] Korea Univ, Inst Convergence Sci, Seoul, South Korea
来源
FRONTIERS IN IMMUNOLOGY | 2020年 / 11卷
基金
新加坡国家研究基金会;
关键词
aminoacyl-tRNA synthetase; threonyl-tRNA synthetase; dendritic cell; interleukin-12; type 1 helper T cells; interferon-γ influenza A virus; IFN-GAMMA; CYTOKINES; KINASES;
D O I
10.3389/fimmu.2020.571959
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-alpha. As T helper (Th) type 1 response and IFN-gamma 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-kappa B p65 subunit along with the degradation of I kappa B proteins and the phosphorylation of MAPKs in DCs. Additionally, MAPK inhibitors markedly recovered the degradation of I kappa B proteins and the increased IL-12 production in TRS-treated DCs, suggesting the involvement of MAPKs as the upstream regulators of NF-kappa B in TRS-induced DC maturation and activation. Importantly, TRS-stimulated DCs significantly increased the populations of IFN-gamma(+)CD4 T cells, and the levels of IFN-gamma 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-gamma 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-gamma(+)-CD4(+) and -CD8(+) T cells as well as secretion level of IFN-gamma, 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.
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页数:13
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