Regulation of CD8+ T cell responses to chronic virus infection

CD8 T 细胞对慢性病毒感染反应的调节

• 批准号: 10551313
• 负责人: JASON Kyle WHITMIRE
• 金额: $ 50.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551313
• 关键词: ATAC-seq; Address; Affect; Apoptosis; Bioinformatics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Aging; Cell Count; Cell physiology; Cells; ChIP-seq; Chromatin; Chronic; Complex; Data; Development; Enhancers; Enzymes; Epigenetic Process; Frequencies; Gene Expression; Genes; Genetic Transcription; Health; Histone H3; Histones; Human; Immune; Immune response; Immunity; Immunoprecipitation; Immunotherapy; Impairment; Infection; Infection Control; Knowledge; Learning; Link; Lymphocytic choriomeningitis virus; Lysine; Maintenance; Mediating; Memory; Methods; Methylation; Methyltransferase; Morbidity - disease rate; Mus; Patients; Persons; Positioning Attribute; Process; Receptor Signaling; Regulation; Regulator Genes; Research; Resistance; Role; Sampling; System; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Transcript; Translating; Viral; Viral Load result; Viral Physiology; Virus; Virus Diseases; chronic infection; demethylation; differential expression; effector T cell; exhaust; exhaustion; histone methylation; improved; inhibitor; mortality; pharmacologic; prevent; programmed cell death protein 1; programs; promoter; receptor; receptor expression; recruit; senescence; transcription factor; transcriptome sequencing

PROJECT SUMMARY Virus-specific CD8+ T cells are essential for immune defenses against many viruses. However, during chronic infections in mice and humans, CD8+ T cells undergo excessive apoptosis or become functionally inactive and unable to resolve infection. T cells fail to eliminate infection due to their sustained expression of inhibitory receptors that actively suppress their antiviral activity. Despite evidence that therapeutic interference with inhibitory receptor signaling can allow some T cells to recover function and reduce viral loads, there continues to be a need for improved methods to prevent T cell exhaustion from occuring or to reverse T cell exhaustion once it sets in. It is now understood that virus-specific T cell senescence and T cell exhaustion are programmed epigenetically and guided by specific sets of transcription factors. Distinct epigenetic processes, including changes in the methylation status of histone-3 lysine-27 (H3K27) in CD8+ T cells, contribute to the formation of memory T cells, as well as functionally inactive subsets during chronic infection. The role of specific enzymes in this process is poorly understood. We recently identified a critical link between CD8+ T cell expression of UTX, an H3K27 demethylase, and impaired CD8+ T cell responses to chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Virus-specific CD8+ T cells lacking UTX showed improved accumulation and maintenace over time, reduced expression of the inhibitory receptors, and were resistant to apoptosis. Our data suggest that UTX restricts virus-specific CD8+ T cell responses by increasing T cell expression of inhibitory receptors, perhaps converting cells with memory potential into functionally exhausted or senescent cells. Our central hypothesis is that UTX controls T cell differentiation through a mixture of demethylase-dependent and demethylase-independent mechanisms that promote gene expression, including at inhibitory receptor loci. In Aim1 we determine the temporal relationship between UTX and CD8+ T cell differentiation into functional or dysfunctional T cell subsets. In Aim2, we investigate the role of UTX-mediated demethylase activity in regulating gene expression and T cell effector functions and maintenance during infection. In Aim3, we explore the role of UTX interacting partners, including T cell-relevant transcription factors and an H3K4 methyltransferase, in guiding T cell differentiation and antiviral functions. Information from this project will be useful for comprehending how epigenetic changes due to histone methylation guide CD8+ T cell exhaustion. Long-term, our research may implicate the use of pharmacologic inhibitors of UTX to improve CD8+ T cell-mediated immune defenses.

项目摘要 病毒特异性CD 8 + T细胞对于针对许多病毒的免疫防御至关重要。但在 在小鼠和人类的慢性感染中，CD 8 + T细胞经历过度凋亡或在功能上变得 不活跃，无法解决感染。T细胞不能消除感染，因为它们持续表达 抑制性受体主动抑制其抗病毒活性。尽管有证据表明， 干扰抑制性受体信号传导可以使一些T细胞恢复功能并减少病毒感染。 负荷，仍然需要改进的方法来防止T细胞耗竭发生或 逆转T细胞衰竭现在了解到，病毒特异性T细胞衰老和T 细胞耗竭是由表观遗传学编程的，并由特定的转录因子组指导。不同 表观遗传过程，包括CD 8 + T细胞中组蛋白-3赖氨酸-27（H3 K27）甲基化状态的变化， 细胞，有助于记忆T细胞的形成，以及慢性炎症期间功能不活跃的亚群。 感染在这一过程中的特定酶的作用知之甚少。我们最近发现了一个关键的 UTX（一种H3 K27脱甲基酶）的CD 8 + T细胞表达与受损的CD 8 + T细胞应答之间的联系 慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染小鼠。病毒特异性CD 8 + T细胞缺乏 UTX显示随着时间的推移，其积累和维持得到改善， 受体，并且对凋亡具有抗性。我们的数据表明UTX限制了病毒特异性CD 8 + T细胞 通过增加抑制性受体的T细胞表达，可能将细胞转化为记忆， 潜在的功能衰竭或衰老的细胞。我们的中心假设是UTX控制T细胞 通过脱甲基酶依赖性和脱甲基酶非依赖性机制的混合来分化， 促进基因表达，包括在抑制性受体位点。在Aim 1中，我们确定时间 UTX与CD 8 + T细胞分化为功能性或功能障碍性T细胞亚群之间的关系。在 目的2，我们研究UTX介导的去甲基化酶活性在调节基因表达和T 感染期间细胞效应子功能和维持。在Aim 3中，我们探讨了UTX相互作用的作用。 包括T细胞相关转录因子和H3 K4甲基转移酶在内的T细胞相关转录因子在引导T细胞 分化和抗病毒功能。从这个项目的信息将有助于理解如何 由于组蛋白甲基化导致的表观遗传变化引导CD 8 + T细胞耗竭。从长远来看，我们的研究可能 涉及UTX的药理学抑制剂用于改善CD 8 + T细胞介导的免疫防御的用途。