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

通过靶向干细胞样 CD8 T 细胞恢复衰老 T 细胞免疫力

• 批准号: 10190752
• 负责人: Tuoqi Wu
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190752
• 关键词: Affect; Age; Aging; Antiviral Agents; Attenuated; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Cessation of life; Characteristics; Chromatin; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Communicable Diseases; Cytokine Signaling; Data; Developed Countries; Development; Elderly; Exhibits; FRAP1 gene; Focus Groups; Genes; Goals; HIV Infections; Health system; Immune; Immunity; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Influenza; Lead; Learning; Lymphocytic choriomeningitis virus; MAP Kinase Gene; Malignant Neoplasms; Mediating; Methods; Modeling; Morbidity - disease rate; Mus; Outcome Study; Pathway interactions; Population; Predisposition; Public Health; Research; Resources; STAT3 gene; Signal Transduction; Stimulus; System; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Therapeutic Effect; Time; Training; Vaccination; Vaccines; Virus Diseases; age related; aged; antiviral immunity; cancer immunotherapy; chronic infection; cytokine; epigenomics; genetic signature; immunosenescence; improved; in vivo; inhibitor/antagonist; interleukin-21; loss of function; mortality; mouse model; novel therapeutic intervention; overexpression; prevent; receptor; response; self-renewal; skills; sound; stem cell differentiation; stem cells; stem-like cell; symposium; transcription factor; transcriptome; transcriptomics; vaccine efficacy

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. !

项目摘要/摘要 免疫衰老是与年龄相关的免疫力下降，会导致更多的人患上 感染和疫苗效力降低。在工业国家中，大多数与流感相关的死亡发生在 老年人。众所周知，慢性病毒感染和与年龄相关的炎症可以促进免疫衰老。 CD8T细胞的免疫衰老的特征是对免疫刺激的反应减弱，而增强 终末分化，共抑制受体表达增加。相比之下，T细胞与干细胞样细胞 这些特征在接种疫苗后存活数十年，并在免疫疗法中显示出优越的治疗效果。 在慢性感染淋巴细胞性脉络膜脑膜炎病毒(LCMV)的小鼠中，我发现了抗病毒CD8T细胞 高表达转录因子TCF1的细胞，这种转录因子类似于干细胞，两者都可以自我更新 补充终末分化程度较高的TCF1low CD8 T细胞。此外，干细胞样CD8T细胞是 对抗慢性LCMV感染和提供更好保护的长效CD8 T细胞至关重要 防止再次感染。因此，干细胞样CD8T细胞是开发改进疫苗和 针对老年人感染的免疫疗法。然而，衰老与炎症增加有关。 年龄相关的炎症是否影响干细胞样CD8T细胞的分化尚不清楚。我的 初步数据表明，在刺激时，老化的CD8 T细胞更容易发生终末分化和 表现出STAT3的激活升高，这是一种转录因子，介导了几种炎症反应的信号转导 细胞因子。我还发现了炎性细胞因子IL-21、STAT3和Sestrin3可能是 干细胞样CD8 T细胞分化的调节因子。因此，我假设与年龄相关的炎症性疾病 STAT3介导的细胞因子信号转导途径抑制老龄小鼠干细胞样CD8T细胞分化 调节Sestrin3的表达，并可靶向恢复衰老的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，并采用切割法- EDGE转录学、表观基因组学和基因编辑方法研究衰老和炎症如何影响 干细胞样CD8T细胞的分化。这项研究的结果将揭示与年龄相关的炎症 细胞因子途径调节干细胞样CD8T细胞在衰老过程中的分化，并促进 旨在通过增强干细胞来恢复衰老T细胞免疫的新治疗策略的开发 如CD8T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 预防和治疗老年人传染病。K99/R00机制将为我提供培训， 有时间和资源在免疫衰老领域站稳脚跟，并通过 获得专家指导以及参加课程、研讨会和会议。 好了！