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

项目总结 艾滋病毒、乙肝病毒和丙型肝炎病毒等病毒的慢性感染仍然是一个重大的全球卫生挑战。在.期间 慢性病毒感染，CD8T细胞无法清除病毒并发展成功能失调的状态，称为 疲惫不堪。耗尽的CD8T细胞，这是首次在慢性淋巴细胞模型中表现出来的 脉络膜脑膜炎病毒(LCMV)感染，逐渐丧失效应功能，上调抑制性受体，以及 表现出代谢失调。免疫疗法未能完全逆转T细胞枯竭或达到 在慢性病毒感染期间持续的病毒控制。因此，有一种尚未得到满足的需要，即制定新的战略，以 克服T细胞耗竭，提高免疫疗法对慢性病毒感染的疗效。虽然 耗尽的CD8T细胞最初被认为是同质的群体，我们和其他人最近这样认为 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 在慢性病毒感染期间补充TCF1低终末耗尽的CD8T细胞。重要的是，这些茎- 像CD8一样，T细胞消耗较少，并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CD8T细胞是一种独立的CD8血统，具有转录和 与终末耗尽的CD8 T细胞不同的表观遗传程序，并受到 转录因子、表观遗传调节因子和细胞因子。这项提议的目标是定义分子 干细胞样CD8 T细胞对抗慢性病毒感染免疫应答的细胞调控机制 并评估通过靶向这些途径提高抗病毒免疫力的策略。使用慢性LCMV感染 模型、尖端代谢分析、多光谱定量成像和独特的小鼠遗传工具，我们 将确定赋予干细胞样CD8T细胞优势的代谢途径和细胞-细胞相互作用 抗病毒免疫和对免疫疗法的反应性。这些结果将为下一步 开发新的干预措施，以促进对慢性病毒感染的持续控制。

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.