Rejuvenating aged T cell immunity by targeting stem cell-like CD8 T cells

项目总结/摘要 免疫衰老，与年龄相关的免疫力下降，导致对以下疾病的易感性增加： 感染和降低疫苗效力。在工业化国家，大多数流感相关死亡发生在 老人已知慢性病毒感染和年龄相关性炎症会促进免疫衰老。 CD 8 T细胞的免疫衰老的特征在于对免疫刺激的应答降低， 终末分化和共抑制剂受体表达升高。相反，具有干细胞样T细胞 这些特征在接种后存活数十年，并在免疫疗法中表现出上级治疗效果。 在淋巴细胞性脉络丛脑膜炎病毒（LCMV）慢性感染的小鼠中，我已经鉴定出抗病毒的CD 8 T 表达高水平转录因子TCF 1的细胞，类似于干细胞，可以自我更新 并补充更具终末分化的TCF 1 low CD 8 T细胞。此外，干细胞样CD 8 T细胞是 对于针对慢性LCMV感染的持久CD 8 T细胞应答至关重要，并提供更好的保护 防止再次感染因此，干细胞样CD 8 T细胞是开发改良疫苗的理想靶标， 老年人感染的免疫疗法。然而，衰老与炎症增加有关。 年龄相关性炎症是否影响干细胞样CD 8 T细胞的分化尚不清楚。我 初步数据表明，在刺激后，老化的CD 8 T细胞更倾向于终末分化， STAT 3是一种转录因子，介导多种炎性细胞因子的信号传导， 细胞因子我还发现了炎症细胞因子IL-21、STAT 3和Sestrin 3可能是 干细胞样CD 8 T细胞分化的调节因子。因此，我假设年龄相关的炎症 STAT 3介导的细胞因子信号传导通过以下途径抑制老年小鼠中干细胞样CD 8 T细胞的分化： 调节Sestrin 3表达，并且可以靶向恢复老化的T细胞免疫。在这项研究中，我将使用 我新开发的体外培养系统和小鼠慢性LCMV感染模型，并采用切割- 边缘转录组学，表观基因组学和基因编辑方法来研究衰老和炎症如何影响 干细胞样CD 8 T细胞的分化。这项研究的结果将揭示年龄相关的炎症是如何发生的。 细胞因子途径调节衰老过程中干细胞样CD 8 T细胞的分化，并促进 开发新的治疗策略，旨在通过增强干细胞- 比如CD 8 T细胞分化我的长期目标是领导一个研究小组，专注于如何利用T细胞 预防和治疗老年人的传染病。K99/R 00机制将为我提供培训， 时间和资源，在免疫衰老领域站稳脚跟，并学习新技能， 获得专家指导以及参加课程、研讨会和会议。 !

Project Summary/Abstract Immunosenescence, the age-associated decline in immunity, leads to increased susceptibility to infection and reduced vaccine efficacies. Most influenza-associated deaths in industrial countries occur among the elderly. Chronic viral infection and age-associated inflammation are known to promote immunosenescence. Immunosenescence of CD8 T cells is characterized by reduced response to immune stimuli, increased terminal differentiation, and elevated expression of co-inhibitor receptors. In contrast, T cells with stem cell-like characteristics survive decades after vaccination and exhibit superior therapeutic effects in immunotherapies. In mice chronically infected by lymphocytic choriomeningitis virus (LCMV), I have identified antiviral CD8 T cells expressing high levels of transcription factor TCF1, which resemble stem cells and can both self-renew and replenish the more terminally differentiated TCF1low CD8 T cells. Moreover, stem cell-like CD8 T cells are critical for long-lasting CD8 T cell response against chronic LCMV infection and provide better protection against re-infection. Thus, Stem cell-like CD8 T cells are ideal targets for developing improved vaccines and immunotherapies against infection in the elderly. However, aging is associated with increased inflammation. Whether age-associated inflammation influences the differentiation of stem cell-like CD8 T cells is unclear. My preliminary data suggest that upon stimulation aged CD8 T cells are more prone to terminal differentiation and exhibits elevated activation of STAT3, a transcription factor that mediates the signaling of several inflammatory cytokines. I have also found evidence that inflammatory cytokine IL-21, STAT3, and Sestrin3 are potential regulators of stem cell-like CD8 T cell differentiation. Thus, I hypothesize that age-associated inflammatory cytokine signaling mediated by STAT3 inhibits the differentiation of stem cell-like CD8 T cells in aged mice by regulating Sestrin3 expression, and can be targeted to rejuvenate aged T cell immunity. In this study, I will use my newly developed in vitro culture system and mouse chronic LCMV infection model, and employ cutting- edge transcriptomic, epigenomic, and gene editing methods to study how aging and inflammation affect the differentiation of stem cell-like CD8 T cells. The results from this study will unveil how age-related inflammatory cytokine pathways regulate the differentiation of stem cell-like CD8 T cells during aging, and facilitate the development of new therapeutic strategies aiming to rejuvenate aged T cell immunity by enhancing stem cell- like CD8 T cell differentiation. My long-term goal is to lead a research group focusing on how to harness T cells to prevent and treat infectious diseases in the elderly. The K99/R00 mechanism will provide me the training, time and resource to gain a sound foothold in the field of immunosenescence and learn new skills through getting expert guidance as well as attending courses, seminars and conferences. !