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

项目摘要 HIV、HBV和HCV等病毒的慢性感染仍然是一个重大的全球健康挑战。期间 慢性病毒感染，CD 8 T细胞不能根除病毒，并发展成功能障碍状态，称为 疲惫不堪耗尽的CD 8 T细胞，其首先在慢性淋巴细胞性白血病小鼠模型中表征。 脉络丛脑膜炎病毒（LCMV）感染，逐渐丧失效应子功能，上调抑制性受体，和 表现出代谢失调免疫疗法不能完全逆转T细胞耗竭或实现 在慢性病毒感染期间持续的病毒控制。因此，需要制定新的战略， 克服T细胞耗竭并增强针对慢性病毒感染的免疫疗法的功效。虽然 耗尽的CD 8 T细胞最初被认为是一个同质的群体，我们和其他人最近 显示TCF 1高抗病毒CD 8 T细胞亚群通过自我更新维持长期抗病毒免疫 以及在慢性病毒感染期间补充TCF 1低终末耗尽的CD 8 T细胞。更重要的是，这一系列... 类似于CD 8 T细胞，其消耗较少，并且介导由各种免疫疗法诱导的应答。我们 已发表的研究已经证明干细胞样CD 8 T细胞是一种单独的CD 8谱系，具有转录和 表观遗传程序与终末耗竭的CD 8 T细胞的表观遗传程序不同，并受到 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 以及调节干细胞样CD 8 T细胞对慢性病毒感染的免疫应答的细胞机制 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，尖端的代谢分析，多光谱定量成像，和独特的小鼠遗传工具，我们 将确定代谢途径和细胞-细胞相互作用，赋予干细胞样CD 8 T细胞其上级 抗病毒免疫和对免疫疗法的反应性。这些结果将为 开发新的干预措施，以诱导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.