Balancing protective immunity and chronic sequelae by resident CD8 T cells

通过常驻 CD8 T 细胞平衡保护性免疫和慢性后遗症

• 批准号: 9981307
• 负责人: Jie Sun
• 金额: $ 56.5万
• 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: 2020-02-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9981307
• 关键词: Ablation; Acute; Acute Disease; Adopted; Adult; CD28 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Child; Chronic; Clinical; Clinical Research; Data; Development; Equilibrium; Etiology; Exhibits; Future; GTP-Binding Protein alpha Subunits, Gs; Goals; Granzyme; Heterogeneity; Immunity; Immunization; Immunology; Immunotherapy; Impairment; In Situ; Infection; Inflammation; Influenza; Influenza Therapeutic; Injury; Interferon Type II; Intervention; Lead; Left; Lung; Maintenance; Mediating; Memory; Molecular; Molecular Target; Morbidity - disease rate; PD-L1 blockade; Parabiosis; Pathogenicity; Pathologic; Patients; Population; Primary Infection; Pulmonary Fibrosis; Recovery; Rejuvenation; Resolution; Role; Science; Signal Transduction; T memory cell; TNF gene; Testing; Tissues; Translating; Vaccine Design; Viral Respiratory Tract Infection; Virus Diseases; acute infection; anti-PD-L1 therapy; antimicrobial; base; design; exhaust; influenza virus vaccine; influenzavirus; insight; mortality; novel; pathogen; programmed cell death protein 1; receptor; response; single-cell RNA sequencing; therapeutic vaccine; transcription factor

Summary/Abstract Tissue-resident memory T cells (TRM) that park within the non-lymphoid tissue provide superior immunity against a variety of pathogens including influenza virus infection. The mechanisms regulating CD8 TRM maintenance, heterogeneity, protective and pathological functions are incompletely understood. Our recent data have identified a novel protective CD8 TRM population that co-exhibits both exhausted and conventional memory CD8 T cell features following acute influenza infection. Unlike the conventional circulating memory CD8 T cells that are maintained in a MHC-I independent way, the survival and maintenance of these PD-1hi TRM cells require persistent MHC-I and TCR signaling. Based on these prelim data, we propose to further elucidate the underlying mechanisms by which these PD-1hi TRM are maintained in the lung. We hypothesize the intrinsic CD28 and PD-1 signaling, specifically in lung-resident CD8 T cells, balances the maintenance, protective function and fibrogenic activities of these PD-1hi TRM following influenza virus infection (Aim 1). Furthermore, we will test the hypothesis that the expression of the transcription factor Klf10 in CD8 T cells is vital for the maintenance and the function of these PD-1hi TRM (Aim 2). In addition, we will determine whether it is possible to uncouple the pathogenic activities from the protective function of TRM, so we may specifically provoke the protective function, but not the pathogenic activities of TRM for future vaccine design and/or immunotherapies (Aim 3). Relevance statement Each year, influenza virus infects 5–10% of adults and 20–30% of children, killing as many as 500,000 people globally. In addition to the acute morbidity and mortality, it is increasingly appreciated that influenza virus infection could lead to the development of chronic lung conditions including pulmonary fibrotic responses. Currently, little is known about the etiology of the development of chronic lung sequelae following influenza virus infection. The successful completion of this study will provide insights for developing interventions to promote the complete recovery of the tissue while minimizing the development of chronic lung conditions following acute respiratory viral infections. Furthermore, understanding the cellular and molecular mechanisms regulating the maintenance of lung protective TRM responses following influenza infection and/or immunization may aid the design of future influenza therapeutics and influenza vaccines.

摘要/摘要 驻留在非淋巴组织内的组织记忆T细胞（TRM）提供了上级免疫力 针对包括流感病毒感染在内的多种病原体。调节CD 8 TRM的机制 维持、异质性、保护和病理功能尚未完全了解。我们最近 数据已经确定了一种新的保护性CD 8 TRM群体，其同时表现出耗竭和 急性流感感染后的常规记忆性CD 8 T细胞特征。不像常规 以MHC-I非依赖性方式维持的循环记忆CD 8 T细胞， 这些PD-1hi TRM细胞的维持需要持续的MHC-I和TCR信号传导。根据这些初步的 数据，我们建议进一步阐明这些PD-1hi TRM维持的潜在机制， 肺我们假设固有的CD 28和PD-1信号传导，特别是在肺部驻留的CD 8 T细胞中， 平衡流感后这些PD-1hi TRM的维持、保护功能和纤维化活性 病毒感染（目的1）。此外，我们还将检验转录因子的表达 CD 8 T细胞中的Klf 10对于这些PD-1hi TRM的维持和功能至关重要（目的2）。另外我们 将决定是否有可能将致病活动与TRM的保护功能分开， 我们可以特异性地激发TRM的保护性功能，而不是致病性活性，用于未来的疫苗 设计和/或免疫疗法（目标3）。 相关性说明 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 在全球除了急性发病率和死亡率之外，越来越多的人认识到，流感病毒 感染可导致包括肺纤维化反应的慢性肺病的发展。 目前，对流感后慢性肺部后遗症的病因学知之甚少 病毒感染。这项研究的成功完成将为制定干预措施提供见解， 促进组织的完全恢复，同时最大限度地减少慢性肺部疾病的发展 急性呼吸道病毒感染后。此外，了解细胞和分子机制 调节流感感染和/或免疫后肺保护性TRM应答的维持 可能有助于设计未来的流感治疗剂和流感疫苗。