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: 10515461
• 负责人: Jie Sun
• 金额: $ 56.97万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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/10515461
• 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 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; Persons; 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; acute infection; anti-PD-L1 therapy; antimicrobial; base; design; exhaust; fibrotic lung; influenza infection; 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 驻留在非淋巴组织中的组织驻留记忆T细胞(TRM)提供了优越的免疫力 抗多种病原体，包括流感病毒感染。CD8TRM的调控机制 维持性、异质性、保护性和病理功能还不完全清楚。我们最近 数据已经确定了一种新的保护性CD8TRM群体，该群体同时表现出疲惫和 急性流感感染后的常规记忆CD8 T细胞特征。不同于传统的 以MHC-I非依赖方式维持的循环记忆CD8 T细胞，存活和 这些PD-1hi TRM细胞的维持需要持续的MHC-I和TCR信号。基于这些前期工作 数据，我们建议进一步阐明维持这些PD-1hi TRM的潜在机制 肺部。我们假设了固有的CD28和PD-1信号，特别是在肺居留的CD8T细胞中， 流感后这些PD-1在TRM中的维持、保护功能和致纤维化活性的平衡 病毒感染(目标1)。此外，我们将检验转录因子的表达 CD8T细胞中的KLF10对这些PD-1hi TRM的维持和功能至关重要(Aim 2)。此外，我们 将决定是否有可能将致病活性与TRM的保护功能分离，因此 对于未来的疫苗，我们可能会特异性地激发TRM的保护功能，但不会激发其致病活性 设计和/或免疫疗法(目标3)。 关联性陈述 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 全球范围内。除了急性发病率和死亡率外，人们越来越认识到流感病毒 感染可能导致慢性肺部疾病的发展，包括肺纤维化反应。 目前，人们对流感后慢性肺部后遗症的病因知之甚少。 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 在急性呼吸道病毒感染之后。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反应的维持 可能有助于未来流感疗法和流感疫苗的设计。