Regenerative Capacity of Anti-Viral Memory CD8 T cells

抗病毒记忆CD8 T细胞的再生能力

• 批准号: 9232971
• 负责人: Marulasiddappa Suresh
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232971
• 关键词: Ablation; Activities of Daily Living; Acute; Aging; Anatomy; Antigen Receptors; Apoptosis; Bacteria; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; CDKN2A gene; Cell Aging; Cell Compartmentation; Cells; Cellular Immunity; Clonal Expansion; Competence; Cyclin-Dependent Kinase Inhibitor; Data; Development; Effector Cell; Elderly; Exhibits; FOXO1A gene; FOXO3A gene; FRAP1 gene; Family; Goals; Health; Homeostasis; Human; Immunity; Immunologic Memory; Immunologic Surveillance; Impairment; Infection; Infection Control; Inflammatory; Interferon Type II; Interleukin-2; Knowledge; Lead; Left; Link; Maintenance; Memory; Memory Loss; Metabolism; Molecular; Mus; Output; Pathway interactions; Phase; Phenocopy; Phenotype; Play; Population; Production; Proliferating; Proteins; Protozoa; Publishing; Quality Control; Repression; Role; Signal Transduction; Stem cells; T memory cell; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tumor Suppressor Proteins; Vaccination; Vaccines; Viral; Virus; Virus Diseases; aged; base; design; innovation; insight; longevity gene; member; mouse model; pathogen; protective efficacy; public health relevance; regenerative; response; self-renewal; senescence; stem; stem-like cell; transcription factor; translational impact; tumor; vaccine efficacy

 DESCRIPTION (provided by applicant): CD8 T cells play crucial roles in control of infections with viruses, intracellular bacteria and protozoa. Acute viral infections typically induce a potent self-renewing population of memory CD8 T cells that persists for decades after infection. Durable protective immunity to repeated infectious insults depends upon the maintenance of a stem-cell-like self-renewing population of memory CD8 T cells with high regenerative capacity i.e. the competence to endure repeated cycles of clonal expansion and differentiation into effector and memory CD8 T cells without attaining senescence. However, human aging is associated with the progressive accumulation of senescent and terminally differentiated memory CD8 T cells (effector memory CD45RA+ve; EMRA) that display poor effector functions and regenerative capacity. The mechanisms that regulate the senescence and regenerative potential of memory CD8 T cells remain poorly understood. The FoxO family of transcription factors mitigates senescence and promotes the regenerative capacity of stem cells. By contrast, the tumor suppressor molecule p16INK4a promotes senescence and limits the regenerative potential of stem cells. Further, p16INK4a expression in T cells is a biomarker of aging, and proliferative arrest of terminally differentiated human T cells is linked to elevated p16INK4a levels. Exciting preliminary data show that: (1) FoxO1 expression is markedly reduced in human senescent EMRA T cells; (2) FoxO1 deficiency results in senescence, regenerative decline of memory CD8 T cells and elevated expression of p16INK4a in mice. Based on these data, in specific aim 1, we will test the hypothesis that "FoxO1 opposes senescence and promotes the regenerative potential of memory CD8 T cells by repressing p16INK4a expression". Not only FoxO1 deficiency, aberrant activation of the mechanistic target of rapamycin (mTOR) is also a prominent feature of cellular senescence and aging. Remarkably, several activities of FoxOs faithfully phenocopy the effects of mTOR inhibition in T cells and stem cells, which supports the idea that the functions of FoxO also include antagonism of mTOR. Based on preliminary data that FoxO1 ablation elevated mTOR activity in memory CD8 T cells, in specific aim 2, we will test the hypothesis that "FoxO1 opposes senescence and promotes the protective capacity of memory CD8 T cells by restraining mTOR activity". This exploratory R21 proposal is innovative because, it seeks to identify a new link between FoxO1, p16 and mTOR in governing the regenerative potential of memory CD8 T cells, and provide mechanistic insights into the dysregulated state and regenerative decline of memory T cells in the elderly. Such new insights into the tractable molecular pathways are predicted to have a substantive and broad impact on human health because, we envision development of strategies to therapeutically modulate the FoxO1-p16/mTOR axis to: (1) restore T-cell homeostasis in the elderly; (2) enhance vaccine-induced CD8 T cell memory; (3) elicit and maintain durable protective cell-mediated immunity in the elderly.

 描述（由申请人提供）：CD8 T 细胞在控制病毒、细胞内细菌和原生动物感染中发挥着至关重要的作用。 自我更新的记忆 CD8 T 细胞群在感染后持续数十年，对反复损伤的持久保护性免疫取决于具有高再生能力的干细胞样自我更新记忆 CD8 T 细胞群的维持。经历克隆扩增和分化为效应和记忆 CD8 T 细胞的重复循环而不会衰老。然而，人类衰老与衰老和终末分化的记忆 CD8 T 细胞（效应记忆）的逐渐积累有关。调节记忆 CD8 T 细胞衰老和再生潜力的机制仍知之甚少。相比之下，肿瘤抑制分子 p16INK4a 会促进衰老并限制干细胞的再生潜力。此外，T 细胞中的 p16INK4a 表达是衰老的生物标志物。人类终末分化 T 细胞的增殖停滞与 p16INK4a 水平升高有关，令人兴奋的初步数据表明：(1) FoxO1 表达在人类衰老 EMRA T 细胞中显着降低；(2) FoxO1 缺陷导致记忆 CD8 的衰老和再生衰退。小鼠中 T 细胞和 p16INK4a 表达升高 基于这些数据，在具体目标 1 中，我们将检验“FoxO1 对抗衰老”的假设。并通过抑制 p16INK4a 表达来促进记忆 CD8 T 细胞的再生潜力。不仅 FoxO1 缺乏，雷帕霉素机制靶点 (mTOR) 的异常激活也是细胞衰老和老化的一个显着特征。值得注意的是，FoxOs 的多种活性忠实地反映了表型复制了 T 细胞和干细胞中 mTOR 抑制的作用，这支持了 FoxO 的功能还包括 mTOR 拮抗作用的观点。数据表明 FoxO1 消除提高了记忆 CD8 T 细胞中的 mTOR 活性，在具体目标 2 中，我们将检验“FoxO1 通过抑制 mTOR 活性来对抗衰老并提高记忆 CD8 T 细胞的保护能力”的假设。这一探索性 R21 提案具有创新性。因为，它试图确定 FoxO1、p16 和 mTOR 之间在控制记忆 CD8 T 细胞再生潜力方面的新联系，并提供对失调状态和老年人记忆 T 细胞的再生衰退。预计这种对易处理分子途径的新见解将对人类健康产生实质性和广泛的影响，因为我们设想开发治疗性调节 FoxO1-p16/mTOR 轴的策略：（ 1）恢复老年人的T细胞稳态；（2）增强疫苗诱导的CD8 T细胞记忆；（3）激发并维持老年人持久的保护性细胞介导的免疫。