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: 10393621
• 负责人: Jie Sun
• 金额: $ 61.69万
• 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/10393621
• 关键词: ATAC-seq; Ablation; Address; Antigen Presentation; B-Lymphocytes; BCL6 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Maintenance; Cells; Cellular Immunity; Cessation of life; Chronic; Cues; Data; Development; Epigenetic Process; Epitopes; Evolution; Exhibits; Future; Gene Expression; Gene Proteins; Generations; Genetic; Goals; Helper-Inducer T-Lymphocyte; Humoral Immunities; Hybrids; Immune response; Immunity; Immunization; In Situ; Influenza; Influenza A virus; Influenza Therapeutic; Influenza vaccination; Invaded; Lung; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Molecular; Mucosal Immunity; Mucous Membrane; Pathway interactions; Plasma; Population; Property; Respiratory Mucosa; Respiratory System; Role; Shapes; Structure of germinal center of lymph node; Structure of parenchyma of lung; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Viral; Virus; Virus Diseases; base; cytokine; design; genetic approach; influenza infection; influenza virus strain; influenzavirus; migration; mucosal site; mucosal vaccination; mucosal vaccine; novel; pathogen; protein expression; response; secondary infection; secondary lymphoid organ; transcription factor; transcriptome sequencing; universal influenza vaccine; universal vaccine; vaccine candidate

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脱保护性体液或细胞免疫 产生的响应。因此，包括强B和弱B的协同免疫应答的诱导是可能的。 针对保守流感病毒表位的T细胞免疫被认为是提供广泛和有效的流感疫苗的关键。 持久的免疫力然而，目前对可能导致癌症的机制和/或途径的理解， 同时刺激强烈的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。 这可能是开发“通用疫苗”的一个关键“瓶颈”， 针对不同流感病毒株的持久和交叉保护免疫力。 我们最近发现，在流感病毒感染后， 清除，共同表现出滤泡辅助细胞（TFH）和组织驻留记忆（TRM）细胞特征。基于其 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)和常驻记忆B（BRM）细胞反应，以及CD 8 TRM群体，显示 介导针对异源流感感染的保护。这些结果提出了一个有趣的想法， 促进强TRH应答将增强针对同源和非同源TRH的保护性粘膜免疫。 异源病毒再激发。我们将在原发性流感之后检验这一想法的“原理证明” 感染和粘膜免疫后的一个有前途的“通用”候选疫苗（Nanovax）。三 提出了具体目标。目的1：阐明TRH细胞特性和调节组的形成机制。目的 2：鉴定调节TRH细胞发育和/或维持的肺环境线索。目标3： 确定TRH细胞在抗IAV再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免疫应答的细胞和分子机制。 细胞记忆反应被适当地编程和/或长期维持在呼吸系统中， 粘膜部位。我们相信，这些研究将大大有助于设计未来的流感治疗方法 和/或有希望的粘膜疫苗，其可以提供针对广谱 流感病毒株（即“通用”疫苗）。