Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung.
Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung.
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DOI：
10.1128/jvi.01211-16
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发表时间：
2016-10-15
影响因子：
5.4
通讯作者：
Gerner W
中科院分区：
文献类型：
--
作者：
Talker SC;Stadler M;Koinig HC;Mair KH;Rodríguez-Gómez IM;Graage R;Zell R;Dürrwald R;Starick E;Harder T;Weissenböck H;Lamp B;Hammer SE;Ladinig A;Saalmüller A;Gerner W
猪是甲型流感病毒的天然宿主，在流感流行病学中起着关键作用。然而，人们对流感引起的T细胞反应知之甚少。我们对流感病毒感染猪的局部和全身T细胞应答进行了全面分析，阐述了动力学和表型以及多功能性（γ干扰素[IFN-γ]、肿瘤坏死因子α [TNF-α]和白细胞介素-2 [IL-2]）和交叉反应性。用H1 N2猪A型流感病毒（FLUAVsw）对共计31头猪进行了肠道感染，并连续实施了安乐死。在感染后（p.i.）的前15天内对肺、气管支气管淋巴结和血液进行采样并且在6周p.i.肺淋巴细胞的离体流式细胞术显示在感染后第6天具有早期效应表型（穿孔素+CD 27+）的增殖（Ki-67+）CD 8 + T细胞增加。早在感染后4天，就可以在肺中检测到低频率的流感病毒特异性产生IFN-γ的CD 4+和CD 8 + T细胞。在连续几天，流感病毒特异性CD 4+和CD 8 + T细胞主要产生IFN-γ和/或TNF-α，在感染后第9天左右达到峰值频率，肺中的含量比气管支气管淋巴结或血液中的含量高出30倍。注射后6周，CD 4+和CD 8+记忆性T细胞在肺组织中聚集。这些细胞显示出不同的细胞因子谱和对异源流感病毒株的体外反应性，所有这些都支持它们对抗猪中异源流感病毒感染的潜力。重要性猪不仅是人类流感病毒感染和疫苗开发的合适大型动物模型，而且在新的大流行毒株的出现中发挥着重要作用。虽然有希望的候选通用疫苗在猪中进行了测试，并且局部T细胞是异源控制的主要相关物，但是在感染部位的T细胞应答的详细和有针对性的分析很少。通过本研究，我们首次详细描述了流感病毒感染猪肺部招募的特异性T细胞的数量、动力学和表型，并且我们可以证明这些细胞的多功能性、交叉反应性和记忆形成。这一点以及随后在猪中开展的工作将加强该物种作为人流感病毒感染的大型动物模型的地位，并将立即有利于疫苗开发，以改善猪流感病毒感染的控制。
Pigs are natural hosts for influenza A viruses and play a critical role in influenza epidemiology. However, little is known about their influenza-evoked T-cell response. We performed a thorough analysis of both the local and systemic T-cell response in influenza virus-infected pigs, addressing kinetics and phenotype as well as multifunctionality (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and cross-reactivity. A total of 31 pigs were intratracheally infected with an H1N2 swine influenza A virus (FLUAVsw) and consecutively euthanized. Lungs, tracheobronchial lymph nodes, and blood were sampled during the first 15 days postinfection (p.i.) and at 6 weeks p.i. Ex vivo flow cytometry of lung lymphocytes revealed an increase in proliferating (Ki-67+) CD8+ T cells with an early effector phenotype (perforin+ CD27+) at day 6 p.i. Low frequencies of influenza virus-specific IFN-γ-producing CD4+ and CD8+ T cells could be detected in the lung as early as 4 days p.i. On consecutive days, influenza virus-specific CD4+ and CD8+ T cells produced mainly IFN-γ and/or TNF-α, reaching peak frequencies around day 9 p.i., which were up to 30-fold higher in the lung than in tracheobronchial lymph nodes or blood. At 6 weeks p.i., CD4+ and CD8+ memory T cells had accumulated in lung tissue. These cells showed diverse cytokine profiles and in vitro reactivity against heterologous influenza virus strains, all of which supports their potential to combat heterologous influenza virus infections in pigs. IMPORTANCE Pigs not only are a suitable large-animal model for human influenza virus infection and vaccine development but also play a central role in the emergence of new pandemic strains. Although promising candidate universal vaccines are tested in pigs and local T cells are the major correlate of heterologous control, detailed and targeted analyses of T-cell responses at the site of infection are scarce. With the present study, we provide the first detailed characterization of magnitude, kinetics, and phenotype of specific T cells recruited to the lungs of influenza virus-infected pigs, and we could demonstrate multifunctionality, cross-reactivity, and memory formation of these cells. This, and ensuing work in the pig, will strengthen the position of this species as a large-animal model for human influenza virus infection and will immediately benefit vaccine development for improved control of influenza virus infections in pigs.
影响因子：
3.7
作者：
Jegaskanda S;Reece JC;De Rose R;Stambas J;Sullivan L;Brooks AG;Kent SJ;Sexton A
通讯作者：
Sexton A