Regulation of CD8+ T cell responses to chronic virus infection

项目总结 病毒特异性CD8+T细胞对许多病毒的免疫防御是必不可少的。然而，在 在小鼠和人类的慢性感染中，CD8+T细胞经历过度的凋亡或功能性 不活跃，不能解决感染。T细胞无法消除感染，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可以使一些T细胞恢复功能并减少病毒 负荷，仍然需要改进的方法来防止T细胞耗尽的发生或 一旦T细胞开始衰竭，就会逆转它的耗竭。现在人们了解到，病毒特异性T细胞衰老和T细胞 细胞耗竭是由表观遗传学编程的，并由特定的转录因子集引导。截然不同 表观遗传过程，包括CD8+T中组蛋白-3赖氨酸-27(H3K27)甲基化状态的变化 细胞，有助于记忆T细胞的形成，以及在慢性疾病中功能不活跃的亚群 感染。人们对特定酶在这一过程中的作用知之甚少。我们最近发现了一名危急的 UTX、H3K27去甲基酶的CD8+T细胞表达与CD8+T细胞反应受损之间的联系 小鼠慢性淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染。病毒特异性CD8+T细胞缺失 UTX随着时间的推移表现出改善的蓄积和维持，减少了抑制物的表达 受体，并对细胞凋亡有抵抗作用。我们的数据表明UTX限制病毒特异性CD8+T细胞 通过增加T细胞抑制受体的表达来做出反应，可能是将有记忆的细胞转化为 有可能转化为功能耗尽或衰老的细胞。我们的中心假设是UTX控制T细胞 通过混合依赖去甲基酶和不依赖去甲基酶的机制进行分化 促进基因表达，包括抑制受体基因的表达。在Aim1中，我们确定时间 UTX与CD8+T细胞分化为功能或功能障碍T细胞亚群的关系在……里面 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 感染期间细胞效应器的功能和维护。在Aim3中，我们探讨了UTX交互的作用 伙伴，包括T细胞相关转录因子和H3K4甲基转移酶，在引导T细胞 分化和抗病毒功能。来自这个项目的信息将有助于理解 组蛋白甲基化引起的表观遗传学改变引导CD8+T细胞耗尽。从长远来看，我们的研究可能 暗示使用UTX的药物抑制剂来提高CD8+T细胞介导的免疫防御。

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.