Roles of tissue-resident helper T cells in mucosal immunity against influenzainfection

组织驻留辅助 T 细胞在针对流感感染的粘膜免疫中的作用

• 批准号: 10515543
• 负责人: Jie Sun
• 金额: $ 51.32万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515543
• 关键词: Roles; tissue; resident; helper; cells

Summary/Abstract The rapid evolution of influenza virus allows the virus to escape from protective humoral or cellular immune responses generated. Therefore, the induction of concerted immune responses including both strong B and T cell immunity against conserved influenza viral epitopes, are believed to be the key to provide broad and long-lasting immunity. However, the current understanding of the mechanisms and/or pathways that can simultaneously stimulate robust B and T cell immunity, particularly at the mucosal sites, are largely elusive. This likely represent a key “bottleneck” for the development of “universal vaccines” that can provide long- lasting and cross-protective immunity against different strains of influenza virus. We have recently identified that a population of lung CD4 helper T (TH) cells developed after influenza viral clearance, co-exhibiting follicular helper (TFH) and tissue-resident memory (TRM) cell features. Based on their gene expression, migration features and functional properties, we termed these cells as tissue-resident T helper cells (TRH). Importantly, TRH cells provide local help for the generation of strong germinal center B (BGC) and resident memory B (BRM) cell responses, as well as a CD8 TRM population that was shown to mediate protection against heterologous influenza infection. These results raise an intriguing idea that the promotion of strong TRH responses will augment protective mucosal immunity against both homologous and heterologous viral re-challenge. We will test the “proof of principle” of this idea following primary influenza infection and after mucosal immunization of a promising “universal” vaccine candidate (Nanovax). Three specific aims are proposed. Aim 1: To unravel the mechanisms shaping TRH cell identity and regulome. Aim 2: To identify lung environmental cues modulating TRH cell development and/or maintenance. Aim 3: To determine the function of TRH cells in the protective immunity against IAV re-challenge. Our long-term goal is to unravel the cellular and molecular mechanisms by which long-term humoral and cellular memory responses are properly programmed and/or long-term maintained in the respiratory mucosal sites. Such studies, we believe, will significantly aid the design of future influenza therapeutics and/or promising mucosal vaccines that can provide long-lasting protection against broad spectrum influenza strains (i.e. “universal” vaccines).

摘要/摘要 流感病毒的快速进化使病毒能够逃离保护性体液或细胞免疫系统 因此，诱导协同免疫反应，包括强 B 和 针对保守流感病毒表位的 T 细胞免疫被认为是提供广泛且有效的免疫应答的关键。 然而，目前对机制和/或途径的了解。 同时刺激强大的 B 细胞和 T 细胞免疫力，特别是在粘膜部位，在很大程度上是难以捉摸的。 这可能是开发“通用疫苗”的一个关键“瓶颈”，这种疫苗可以提供长期的支持。 针对不同流感病毒株的持久和交叉保护性免疫力。 我们最近发现，流感病毒感染后，肺中出现了一群 CD4 辅助 T (TH) 细胞 清除、共表现滤泡辅助细胞 (TFH) 和组织驻留记忆 (TRM) 细胞特征。 基因表达、迁移特征和功能特性，我们将这些细胞称为组织驻留 T 辅助细胞 (TRH) 重要的是，TRH 细胞为强大的生发中心 B 的生成提供局部帮助。 (BGC) 和常驻记忆 B (BRM) 细胞反应，以及 CD8 TRM 群体 介导针对异源流感感染的保护作用这些结果提出了一个有趣的想法： 促进强烈的 TRH 反应将增强针对同源和 我们将在原发性流感之后测试这一想法的“原理证明”。 感染以及在有前途的“通用”候选疫苗（Nanovax）的粘膜免疫后。 提出了具体目标 目标 1：揭示形成 TRH 细胞身份和调节组的机制。 2：确定调节 TRH 细胞发育和/或维持的肺部环境线索 目标 3： 确定 TRH 细胞在针对 IAV 再次攻击的保护性免疫中的功能。 我们的长期目标是揭示长期体液和细胞因子的细胞和分子机制。 细胞记忆反应在呼吸系统中被正确编程和/或长期维持 我们相信，此类研究将极大地帮助设计未来的流感疗法。 和/或有前途的粘膜疫苗，可以提供持久的广谱保护 流感毒株（即“通用”疫苗）。