Molecular regulation of protective CD8 immunity against influenza infection

摘要/摘要 驻留在非淋巴组织中的组织驻留记忆T细胞(TRM)提供了优越的免疫力 对包括流感病毒感染在内的各种病原体与循环记忆T的比较 细胞。 目前， 调控CD8 TRM编程、维持的分子和代谢机制 组织中的功能还没有完全被理解。揭开肺的新机制 流感感染后保护性TRM反应被调节可能有助于未来流感的设计 治疗学和/或流感疫苗。这笔拨款的长期目标是研究分子 呼吸道保护性CD8 T细胞免疫发展的调控机制 流感感染。 我们最近发现了转录因子Bhlhe40，它在调节适应性方面起着核心作用 和流感特异性CD8TRM的功能。在这个应用中，我们假设非规范的TGFbR 信号通过TAK1/Gadd45b依赖的途径促进Bhlhe40的表达和TRM 线粒体健康，从而促进TRM对流感的维持和保护功能 感染。提出了三个具体目标：目标1：确定 Bhlhe40促进流感感染后的保护性TRM反应。目标2：阐明基因的作用 TAK1-Gadd45b途径介导的非典型TGFBR信号在调节TRM发育中的作用 和/或维护。目的3：明确TAK1-Gadd45b-Gadd45b调节线粒体适合性的作用。 Bhlhe40途径，在调节TRM反应和保护功能中发挥作用。 每年，流感病毒感染5%-10%的成年人和20%-30%的儿童，导致多达50万人死亡 全球各地的人。了解调节形成和/或的细胞和分子机制 在流感感染和/或免疫后维持肺保护性TRM反应可能有助于 未来流感疗法和新型流感疫苗的设计。

Summary/Abstract Tissue-resident memory T cells (TRM) that reside within the non-lymphoid tissues provide superior immunity against a variety of pathogens including influenza virus infection compared to the circulating memory T cells. Currently, the molecular and metabolic mechanisms regulating CD8 TRM programming, maintenance and functions in the tissue are incompletely understood. Unravelling novel mechanisms by which lung protective TRM responses are regulated following influenza infection may aid the design of future influenza therapeutics and/or influenza vaccines. The long-term objective of this grant is to investigate the molecular mechanisms regulating the development of protective CD8 T cell immunity in the respiratory tract during influenza infection. We recently have identified the transcription factor, Bhlhe40, plays a central role in regulating the fitness and function of influenza-specific CD8 TRM. In this application, we hypothesize that non-canonical TGFbR signaling, through TAK1/Gadd45b-dependent pathway, facilitates Bhlhe40 expression and TRM mitochondrial health, thereby promoting the maintenance and protective functions of TRM against influenza infection. Three specific Aims are proposed: Aim 1: To determine the underlying mechanisms by which Bhlhe40 promotes protective TRM responses following influenza infection. Aim 2: To elucidate the roles of non-canonical TGFBR signaling, mediated through TAK1-Gadd45b pathway, in regulating TRM development and/or maintenance. Aim 3: To define the roles of mitochondrial fitness, modulated by TAK1-Gadd45b- Bhlhe40 pathway, in regulating TRM responses and protective function. Each year, influenza virus infects 5–10% of adults and 20–30% of children, killing as many as 500,000 people globally. Understanding the cellular and molecular mechanisms regulating the formation and/or maintenance of lung protective TRM responses following influenza infection and/or immunization may aid the design of future influenza therapeutics and novel influenza vaccines.