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 病毒特异性的CD8+ T细胞对于针对许多病毒的免疫防御至关重要。但是，期间 小鼠和人类的慢性感染，CD8+ T细胞经历过多的凋亡或在功能上变得 不活跃，无法解决感染。 T细胞由于其持续的表达而无法消除感染 积极抑制其抗病毒活性的抑制受体。尽管有证据表明治疗 干扰抑制受体信号传导可以使某些T细胞恢复功能并降低病毒 负载，仍需要改进的方法来防止T细胞耗尽的发生或 T细胞置入后，反向T细胞耗尽。现在可以理解，病毒特异性的T细胞衰老和T 细胞耗尽是表观遗传编程的，并由特定的转录因子集进行指导。清楚的 表观遗传过程，包括CD8+ T中组蛋白-3赖氨酸-27（H3K27）的甲基化状态的变化 细胞，有助于记忆T细胞的形成，以及在慢性期间功能无效的子集 感染。特定酶在此过程中的作用知之甚少。我们最近确定了一个关键 CD8+ T细胞表达UTX，H3K27脱甲基酶和CD8+ T细胞反应受损之间的联系 在小鼠中感染慢性淋巴细胞绒毛膜炎病毒（LCMV）。病毒特异性CD8+ T细胞缺乏 随着时间的流逝，UTX表现出改善的积累和维护，抑制作用的表达降低 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CD8+ T细胞 通过增加抑制受体的T细胞表达来响应，也许会与记忆转化细胞 潜在的功能耗尽或衰老的细胞。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独立的机制的混合物分化 促进基因表达，包括在抑制受体位点。在AIM1中，我们确定时间 UTX与CD8+ T细胞之间的关系分化为功能或功能失调的T细胞子集。在 AIM2，我们研究了UTX介导的脱甲基酶活性在调节基因表达和T的作用 细胞效应子功能和感染过程中的维护。在AIM3中，我们探索UTX交互的作用 在引导T细胞中，包括与T细胞相关的转录因子和H3K4甲基转移酶的合作伙伴 分化和抗病毒功能。该项目的信息将对理解如何 由于组蛋白甲基化指南CD8+ T细胞耗尽而引起的表观遗传学变化。长期，我们的研究可能 暗示使用UTX的药理学抑制剂来改善CD8+ T细胞介导的免疫防御能力。