Xue Chunxue, Wen Mingjie, Bao Linlin, Li Hui, Li Fengdi, Liu Meng, Lv Qi, An Yunqing, Zhang Xulong, Cao Bin
Department of Respiratory and Critical Care Medicine, Beijing Luhe Hospital, Capital Medical University, Beijing, China.
Department of Immunology, The Research Centre of Microbiome, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Front Immunol. 2017 Aug 31;8:1054. doi: 10.3389/fimmu.2017.01054. eCollection 2017.
The influenza A (H1N1) pdm09 virus remains a critical global health concern and causes high levels of morbidity and mortality. Severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the major outcomes among severely infected patients. Our previous study found that interleukin (IL)-17A production by humans or mice infected with influenza A (H1N1) pdm09 substantially contributes to ALI and subsequent morbidity and mortality. However, the cell types responsible for IL-17A production during the early stage of severe influenza A (H1N1) pdm09 infection remained unknown. In this study, a mouse model of severe influenza A (H1N1) pdm09 infection was established. Our results show that, in the lungs of infected mice, the percentage of γδT cells, but not the percentages of CD4Th and CD8Tc cells, gradually increased and peaked at 3 days post-infection (dpi). Further analysis revealed that the Vγ4γδT subset, but not the Vγ1γδT subset, was significantly increased among the γδT cells. At 3 dpi, the virus induced significant increases in IL-17A in the bronchoalveolar lavage fluid (BALF) and serum. IL-17A was predominantly secreted by γδT cells (especially the Vγ4γδT subset), but not CD4Th and CD8Tc cells at the early stage of infection, and IL-1β and/or IL-23 were sufficient to induce IL-17A production by γδT cells. In addition to secreting IL-17A, γδT cells secreted interferon (IFN)-γ and expressed both an activation-associated molecule, natural killer group 2, member D (NKG2D), and an apoptosis-associated molecule, FasL. Depletion of γδT cells or the Vγ4γδT subset significantly rescued the virus-induced weight loss and improved the survival rate by decreasing IL-17A secretion and reducing immunopathological injury. This study demonstrated that, by secreting IL-17A, lung Vγ4γδT cells, at least, in part mediated influenza A (H1N1) pdm09-induced immunopathological injury. This mechanism might serve as a promising new target for the prevention and treatment of ALI induced by influenza A (H1N1) pdm09.
甲型H1N1流感pdm09病毒仍然是全球重大公共卫生问题，可导致高发病率和高死亡率。严重急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是严重感染患者的主要结局。我们之前的研究发现，感染甲型H1N1流感pdm09的人或小鼠产生的白细胞介素（IL）-17A在很大程度上导致了ALI及随后的发病率和死亡率。然而，在甲型H1N1流感pdm09严重感染早期负责产生IL-17A的细胞类型尚不清楚。在本研究中，建立了甲型H1N1流感pdm09严重感染的小鼠模型。我们的结果表明，在感染小鼠的肺中，γδT细胞的百分比逐渐增加，并在感染后3天（dpi）达到峰值，而CD4Th和CD8Tc细胞的百分比则没有变化。进一步分析显示，在γδT细胞中，Vγ4γδT亚群而非Vγ1γδT亚群显著增加。在3 dpi时，病毒导致支气管肺泡灌洗液（BALF）和血清中IL-17A显著增加。在感染早期，IL-17A主要由γδT细胞（尤其是Vγ4γδT亚群）分泌，而非CD4Th和CD8Tc细胞，并且IL-1β和/或IL-23足以诱导γδT细胞产生IL-17A。除了分泌IL-17A外，γδT细胞还分泌干扰素（IFN）-γ，并表达激活相关分子自然杀伤细胞2成员D（NKG2D）和凋亡相关分子FasL。γδT细胞或Vγ4γδT亚群的耗竭通过减少IL-17A分泌和减轻免疫病理损伤，显著挽救了病毒诱导的体重减轻并提高了存活率。本研究表明，肺Vγ4γδT细胞至少部分通过分泌IL-17A介导了甲型H1N1流感pdm09诱导的免疫病理损伤。这一机制可能成为预防和治疗甲型H1N1流感pdm09诱导的ALI的一个有前景的新靶点。
