GITRL/GITR信号轴调控Th22细胞在EV71感染导致重症手足口病中的作用研究

Enterovirus 71 (EV71) is the most virus in children with hand, foot and mouth disease (HFMD), which can lead to severe complications and even death. GITR (Glucocorticoid-induced tumor necrosis factor receptor, GITR) belongs to the member of the tumor necrosis factor receptor superfamily, combining with GITR ligand (GITRL), can stimulate effective T cell activation and proliferation. Th22 cells play a crucial role in the viral diseases. Our previous studies found that the frequency of Th22 cells was significantly increased in children with severe HFMD caused by EV71 infection, GITRL expression on dendritic cells (DC) was up-regulated by EV71 infection, and GITRL could promote the generation of Th22 cells, thus we speculated that GITRL/GITR signal axis could promote the generation of Th22 cells that exacerbate the development and progression of severe HFMD caused by EV71 infection. Therefore, to provide experimental bases for further elucidating the pathogenesis of severe HFMD caused by EV71 infection and looking for novel intervention measures, we will further explore the possible pathways and mechanisms including the up-regulation of GITRL expression on DC and the generation of Th22 cells regulated by GITRL/GITR signal axis in EV71 infection, and analyze the roles of Th22 cells in the severe wild and GITR knock-down suckling mice model with EV71 infection.

肠道病毒71型（EV71）是导致儿童重症手足口病（HFMD）发生甚至死亡的最重要病毒。GITR属于肿瘤坏死因子受体超家族成员，与其配体GITRL结合，具有刺激效应性T细胞活化增殖作用，Th22细胞在病毒性疾病中发挥重要作用。我们前期研究发现EV71感染可导致重症HFMD患儿的Th22细胞显著增加，促进树突状细胞（DC）上调GITRL表达，GITRL能促进Th22细胞产生，由此我们推测GITRL/GITR信号轴能促进Th22细胞产生而加剧EV71感染导致重症HFMD的发生发展。因此我们拟探索EV71感染DC上调GITRL表达及GITRL/GITR信号轴调控Th22细胞产生的可能途径及其机制，分析Th22细胞在EV71感染致重症发生的野生型和GITR基因Knock-down乳鼠模型中的作用，为进一步阐明EV71感染致重症HFMD的发病机制和寻找新的干预措施提供实验依据。

肠道病毒71型（EV71）是导致儿童重症手足口病（HFMD）发生甚至死亡的最重要病毒。重症患儿病情进展较快，目前没有较好的评价指标。GITR属于肿瘤坏死因子受体超家族成员，与其配体GITRL结合，具有刺激效应性T细胞活化增殖作用，而Th22细胞在病毒性疾病中发挥重要作用。我们利用流式细胞技术和PCR等实验方法，发现EV71感染可导致HFMD患儿的外周血中Th22细胞显著增加，抗原提呈细胞（如DC）表面GITRL表达上调；在细胞因子的存在下GITRL能有效促进Th22细胞产生，EV71病毒体外可促进DC上调GITRL，进而促进Th22细胞分化，并涉及AhR信号的活化。本项目初步探讨EV71通过上调抗原提呈细胞（APCs）表面GITRL表达及GITRL/GITR信号轴调控Th22细胞产生的作用和机制，具体的关键机制将进一步深入分析，为进一步阐明EV71感染致重症HFMD的发病机制和重症HFMD发生提供新的思路。