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

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: 10065060
• 负责人: Jie Sun
• 金额: $ 51.5万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10065060
• 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; 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; genetic profiling; 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 流感病毒的快速演变使该病毒能够从受保护的体液或细胞免疫中逃脱 产生的响应。因此，诱导一致的免疫反应，包括强B和 T细胞免疫对构成的影响构成的病毒表现，被认为是提供广泛和广泛的关键 持久的免疫力。但是，当前对机制和/或途径的理解 类似地，刺激强大的B和T细胞免疫异位，尤其是在粘膜部位，在很大程度上是弹性的。 这可能是开发“通用疫苗”的关键“瓶颈”，可以提供长期 持久和交叉保护的免疫学针对不同的影响菌病毒。 我们最近确定，在影响力病毒后，肺CD4辅助剂t（Th）细胞形成 清除率，共同检测的卵泡辅助器（TFH）和组织居民记忆（TRM）细胞特征。基于他们的 基因表达，迁移特征和功能特性，我们将这些细胞称为组织居民T 辅助细胞（TRH）。重要的是，TRH细胞为生成强生发中心B的生成提供了局部帮助 （BGC）和居民记忆B（BRM）细胞反应以及CD8 TRM种群 介导对异源影响的保护。这些结果提出了一个有趣的想法 促进强大的TRH反应将增强受保护的粘膜免疫，以应对同源和 异源病毒重新挑战。我们将在主要影响力之后测试该想法的“原理证明” 感染和粘膜免疫后，有望“普遍”疫苗候选者（Nanovax）。三 提出了具体目标。目标1：揭示塑造TRH细胞身份和调节的机制。目的 2：确定调节TRH细胞开发和/或维护的肺环境提示。目标3：到 确定TRH细胞在受保护的免疫力中针对IAV重新挑战的功能。 我们的长期目标是揭示长期体液和长期体液和分子机制 细胞记忆反应适当地编程和/或长期维护的呼吸道 粘膜部位。我们认为，这样的研究将大大帮助未来影响的设计 和/或承诺粘膜疫苗，可以为广泛范围提供长期保护 流感菌株（即“通用”疫苗）。