David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Centergrid.412750.5, Rochester, New York, USA.
Center for Immunology, Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
J Virol. 2021 Jul 26;95(16):e0084121. doi: 10.1128/JVI.00841-21.
Lung-localized CD4 T cells play a critical role in the control of influenza virus infection and can provide broadly protective immunity. However, current influenza vaccination strategies primarily target influenza hemagglutinin (HA) and are administered peripherally to induce neutralizing antibodies. We have used an intranasal vaccination strategy targeting the highly conserved influenza nucleoprotein (NP) to elicit broadly protective lung-localized CD4 T cell responses. The vaccine platform consists of a self-assembling nanolipoprotein particle (NLP) linked to NP with an adjuvant. We have evaluated the functionality, localization, and persistence of the T cells elicited. Our study revealed that intranasal vaccination elicits a polyfunctional subset of lung-localized CD4 T cells that persist long term. A subset of these lung CD4 T cells localize to the airway, where they can act as early responders following encounter with cognate antigen. Polyfunctional CD4 T cells isolated from airway and lung tissue produce significantly more effector cytokines IFN-γ and TNF-α, as well as cytotoxic functionality. When adoptively transferred to naive recipients, CD4 T cells from NLP:NP-immunized lung were sufficient to mediate 100% survival from lethal challenge with H1N1 influenza virus. Exploiting new, more efficacious strategies to potentiate influenza virus-specific immune responses is important, particularly for at-risk populations. We have demonstrated the promise of direct intranasal protein vaccination to establish long-lived immunity in the lung with CD4 T cells that possess features and positioning in the lung that are associated with both immediate and long-term immunity, as well as demonstrating direct protective potential.
肺局部的 CD4 T 细胞在控制流感病毒感染中发挥着关键作用，并能提供广泛的保护性免疫。然而，目前的流感疫苗接种策略主要针对流感血凝素 (HA)，并通过外周途径接种以诱导中和抗体。我们使用了一种针对高度保守的流感核蛋白 (NP) 的鼻腔内疫苗接种策略，以引发广泛的保护性肺局部 CD4 T 细胞反应。疫苗平台由与 NP 连接的自组装纳米脂蛋白颗粒 (NLP) 和佐剂组成。我们已经评估了所引发的 T 细胞的功能、定位和持久性。我们的研究表明，鼻腔内接种会引发长期存在的多功能肺局部 CD4 T 细胞亚群。这些肺 CD4 T 细胞中的一部分定位于气道，在遇到同源抗原后，它们可以作为早期反应者发挥作用。从气道和肺组织中分离出的多功能 CD4 T 细胞产生的效应细胞因子 IFN-γ 和 TNF-α 以及细胞毒性功能显著增加。当过继转移到未感染的受体时，来自 NLP:NP 免疫肺的 CD4 T 细胞足以介导对 H1N1 流感病毒致死性挑战的 100%存活。利用新的、更有效的策略来增强流感病毒特异性免疫反应非常重要，尤其是对于高危人群。我们已经证明了直接鼻腔内蛋白疫苗接种在肺部建立长寿免疫的潜力，这种免疫由具有在肺部的特征和定位的 CD4 T 细胞介导，这些特征和定位与即时和长期免疫以及直接的保护潜力有关。
