Molecular regulation of protective CD8 immunity against influenza infection

总结/摘要 驻留在非淋巴组织内的组织驻留记忆T细胞（TRM）提供上级免疫 与循环记忆T相比， 细胞 目前， 调节CD 8 TRM编程、维持 组织中的功能还不完全清楚。揭示了肺 在流感感染后调节保护性TRM反应可能有助于设计未来的流感 治疗剂和/或流感疫苗。这项资助的长期目标是研究 免疫调节机制的发展，保护性CD 8 T细胞免疫的呼吸道中， 流感感染。 我们最近发现转录因子Bhlhe 40在调节适应性中起着核心作用， 和流感特异性CD 8 TRM的功能。在本申请中，我们假设非典型TGF β R 通过TAK 1/Gadd 45 b依赖性途径的信号传导促进Bhlhe 40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 Bhlhe 40促进流感感染后的保护性TRM应答。目标2：阐明 TAK 1-Gadd 45 b通路介导的非经典TGFBR信号转导在TRM发生中的作用 和/或维护。目的3：确定线粒体适应性的作用，由TAK 1-Gadd 45 b-1调节。 Bhlhe 40通路在调节TRM反应和保护功能中的作用。 每年，流感病毒感染5-10%的成年人和20-30%的儿童，造成多达50万人死亡 全球的人。了解调节形成和/或 在流感感染和/或免疫接种后维持肺保护性TRM应答可有助于 设计未来的流感治疗剂和新型流感疫苗。

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.