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

摘要/摘要 流感病毒的快速进化使病毒能够逃脱保护性体液或细胞免疫。 已生成响应。因此，包括强B和强B在内的协同免疫反应的诱导 针对保守的流感病毒表位的T细胞免疫被认为是提供广泛和 持久的豁免权。然而，目前对机制和/或途径的理解 同时激发强大的B和T细胞免疫，特别是在粘膜部位，在很大程度上是难以捉摸的。 这很可能是“通用疫苗”发展的一个关键“瓶颈”，这种疫苗可以提供长期的 针对不同流感病毒株的持久和交叉保护免疫。 我们最近发现，在流感病毒感染后，肺内出现了一群CD4辅助T(TH)细胞 清除，同时表现出滤泡助手(TFH)和组织驻留记忆(TRM)细胞的特征。基于他们的 这些细胞的基因表达、迁移特征和功能特性我们称之为组织驻留T细胞 辅助细胞(TRH)。重要的是，TRH细胞为强生发中心B的产生提供局部帮助 (BGC)和驻留记忆B(BRM)细胞反应，以及CD8 TRM群体显示 对异源流感感染的中介保护。这些结果提出了一个耐人寻味的想法 促进强大的TRH反应将增强针对同源和 异源病毒再次挑战。我们将在原发流感之后测试这一想法的“原则证明” 在感染和粘膜免疫后，有希望的“通用”候选疫苗(Nanovax)。三 提出了具体的目标。目的1：揭示TRH细胞特性和调节组的形成机制。目标 2：确定调节TRH细胞发育和/或维持的肺环境信号。目标3：实现 确定TRH细胞在抵抗IAV再攻击的保护性免疫中的作用。 我们的长期目标是解开细胞和分子机制，通过这些机制长期体液和 细胞记忆反应在呼吸中被适当地编程和/或长期维持 粘膜部位。我们相信，这样的研究将极大地帮助设计未来的流感疗法。 和/或前景看好的黏膜疫苗，可以提供对广谱病毒的长期保护 流感病毒株(即“通用”疫苗)。

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).