Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection

编程干细胞样 CD8 T 细胞以增强针对慢性病毒感染的抗病毒免疫力

• 批准号: 10687970
• 负责人: Tuoqi Wu
• 金额: $ 54.09万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687970
• 关键词: Affect; Anti-CD40; Antigen Targeting; Antiviral Response; BACH2 gene; BCL6 gene; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Shape; Cells; Cellular Metabolic Process; Chronic; Data; Dendritic Cells; Development; Endowment; Energy Metabolism; Environment; Epigenetic Process; Exhibits; Flow Cytometry; Foundations; Genetic Transcription; Goals; HIV; HIV Infections; Hepatitis B Virus; Hepatitis C virus; Heterogeneity; Human; Immune response; Immunity; Immunotherapy; Interferon Type I; Intervention; Knockout Mice; Lymphocytic choriomeningitis virus; Lymphoid Tissue; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Mus; Mutant Strains Mice; PD-1 blockade; Pathway interactions; Patients; Persons; Poly I-C; Population; Preventative vaccination; Primates; Public Health; Publications; Publishing; Reporter; Respiration; Role; SIV; Subunit Vaccines; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Treatment Efficacy; Vaccine Therapy; Vaccines; Viral; Viral Cancer; Viremia; Virus; Virus Diseases; XCR1 gene; anti-viral efficacy; antiviral immunity; chronic infection; cytokine; exhaust; exhaustion; global health; improved; metabolic fitness; mouse genetics; mouse model; novel; programs; quantitative imaging; receptor; response; self-renewal; stem; stem-like cell; tool; transcription factor

PROJECT SUMMARY Chronic infection by viruses such as HIV, HBV, and HCV remains a major global health challenge. During chronic viral infection, CD8 T cells fail to eradicate the virus and develop into a dysfunctional state, termed exhaustion. Exhausted CD8 T cells, which were first characterized in mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, progressively lose effector function, upregulate inhibitory receptors, and exhibit dysregulated metabolism. Immunotherapies fail to completely reverse T-cell exhaustion or achieve sustained viral control during chronic viral infection. Thus, there is an unmet need to develop new strategies to overcome T-cell exhaustion and enhance the efficacy of immunotherapy against chronic viral infection. Although exhausted CD8 T cells were initially thought to be a homogeneous population, we and others have recently shown that a TCF1high antiviral CD8 T cell subset maintains long-term antiviral immunity through self-renewal and replenishing TCF1low terminally exhausted CD8 T cells during chronic viral infection. Importantly, these stem- like CD8 T cells are less exhausted and mediate the response induced by various immunotherapies. Our published studies have demonstrated stem-like CD8 T cells as a separate CD8 lineage with transcriptional and epigenetic programs that are distinct from those of terminally exhausted CD8 T cells and are tightly regulated by transcription factors, epigenetic regulators, and cytokines. The goal of this proposal is to define the molecular and cellular mechanisms regulating the immune response of stem-like CD8 T cells against chronic viral infection and evaluate strategies to improve antiviral immunity by targeting these pathways. Using chronic LCMV infection model, cutting-edge metabolic assay, multispectral quantitative imaging, and unique mouse genetic tools, we will identify the metabolic pathways and cell-cell interactions that endow stem-like CD8 T cells with their superior antiviral immunity and responsiveness to immunotherapies. These results will lay the foundation for the development of novel interventions to induce sustained control over chronic viral infections.

项目概要 HIV、HBV 和 HCV 等病毒的慢性感染仍然是全球主要的健康挑战。期间 慢性病毒感染时，CD8 T 细胞无法根除病毒并发展为功能失调状态，称为 精疲力尽。耗竭的 CD8 T 细胞，首次在慢性淋巴细胞性白血病小鼠模型中得到表征 脉络丛脑膜炎病毒 (LCMV) 感染，效应器功能逐渐丧失，抑制性受体上调， 表现出代谢失调。免疫疗法无法完全逆转 T 细胞耗竭或实现 慢性病毒感染期间持续的病毒控制。因此，制定新战略的需求尚未得到满足 克服T细胞耗竭并增强免疫疗法针对慢性病毒感染的功效。虽然 耗尽的 CD8 T 细胞最初被认为是同质群体，我们和其他人最近发现 研究表明，TCF1 高抗病毒 CD8 T 细胞亚群通过自我更新维持长期抗病毒免疫力 以及在慢性病毒感染期间补充 TCF1low 最终耗尽的 CD8 T 细胞。重要的是，这些干 CD8 T 细胞消耗较少，可介导各种免疫疗法诱导的反应。我们的 已发表的研究表明干细胞样 CD8 T 细胞是一个独立的 CD8 谱系，具有转录和 表观遗传程序与最终耗尽的 CD8 T 细胞不同，并且受到严格调控 转录因子、表观遗传调节因子和细胞因子。该提案的目标是定义分子 干细胞样CD8 T细胞对抗慢性病毒感染免疫反应的细胞机制调节 并评估通过针对这些途径来提高抗病毒免疫力的策略。使用慢性 LCMV 感染 模型、尖端代谢测定、多光谱定量成像和独特的小鼠遗传工具，我们 将确定代谢途径和细胞间相互作用，赋予干样 CD8 T 细胞优越的性能 抗病毒免疫力和对免疫疗法的反应。这些结果将为 开发新的干预措施以持续控制慢性病毒感染。