Regulation of CD8 T Cell Immunity by CDK Inhibitor p27Kip1

CDK 抑制剂 p27Kip1 对 CD8 T 细胞免疫的调节

• 批准号: 7460476
• 负责人: Marulasiddappa Suresh
• 金额: $ 36万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460476
• 关键词: Ablation; Activities of Daily Living; Acute; Antigens; Applications Grants; Arenavirus; Bone Marrow; CD8B1 gene; Cell Cycle; Cell Cycle Arrest; Cell Differentiation process; Cells; Chimera organism; Competence; Cues; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cytomegalovirus; Development; Disease; Effector Cell; Exhibits; Family; Gene Expression; Genetic; Goals; HIV; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Human; Human Herpesvirus 4; Immunity; Immunotherapeutic agent; Immunotherapy; Knock-out; Knockout Mice; Lassa fever virus; Lymphocytic choriomeningitis virus; Memory; Modality; Modification; Molecular; Molecular Target; Mus; Numbers; Pathway interactions; Play; Process; Proliferating; Property; Public Health; Range; Rate; Regulation; Role; Signal Pathway; T memory cell; T-Lymphocyte; Testing; Time; Transgenic Organisms; Vaccines; Viral; Virus Diseases; Week; base; cytokine; improved; in vivo; influenzavirus; inhibitor/antagonist; insight; mouse model; novel; pathogen; precursor cell; programs; response; stem; transcription factor; vaccination strategy

DESCRIPTION (provided by applicant): CD8 T cells play a crucial role in defense against viral infections like HIV, hepatitis B and C, Epstein Barr virus, cytomegalovirus, and arenaviruses. A major drive therefore has been to develop novel vaccination strategies that can elicit potent CD8 T cell memory and engender effective protective immunity against these viral pathogens. Recent studies have indicated that memory CD8 T cell precursors are present as a subset of effector cells at the peak of the primary T cell response. However, unlike competent memory cells, these memory precursors are in a state of cell cycle arrest; they lack the ability to self renew by homeostatic proliferation or proliferate in response to antigen re-call, and provide poor protective immunity. These memory precursors embark on a program of differentiation to become competent memory cells by a process lasting up to several weeks after antigen clearance. Despite the recognition that effector to memory differentiation is a rate-limiting step in the development of CD8 T cell-dependent protective immunity, the mechanisms underlying the induction and subsequent reversal of proliferative block in memory precursors are poorly defined. Our studies using the mouse model of lymphocytic choriomeningitis virus (LCMV) have shown that genetic deficiency of cyclin dependent kinase inhibitor p27Kip1 not only accelerated the differentiation of memory cells from effector CD8 T cells, but also significantly increased the magnitude of CD8 T cell memory. Based on these findings, our central hypothesis is: p27Kip1 impedes differentiation of memory CD8 T cells from primary effector CD8 T cells by opposing cell cycle re-entry in response to mitogenic cues. We further hypothesize that memory CD8 T cell differentiation including p27Kip1 expression is regulated by the upstream FOXO transcription factors. This proposal focuses on elucidating the key roles of FOXO/p27Kip1 pathway in regulating the differentiation of memory CD8 T cells through these specific aims: 1) To test the hypothesis that effects of p27Kip1 in regulating memory cell differentiation are CD8 T-cell autonomous 2) To test the hypothesis that FOXO transcription factors regulate differentiation of memory CD8 T cells. Aims 1 and 2 will utilize complementary approaches including TCR transgenic (tg) mice, bone marrow chimeras, mice that are conditionally deficient for p27Kip1 or FOXOs in T cells, and inducible p27Kip1/FOXO tg mice to determine the in vivo role of p27Kip1 and FOXOs in regulating the dynamics of phenotypic and functional modifications that occur in CD8 T cells during differentiation from effectors to competent memory cells. These studies would provide critical insight into the mechanisms governing memory cell differentiation, and also have the potential to identify p27Kip1 and FOXO as molecular targets for development of novel immunotherapies to accelerate and enhance the induction of vaccine-induced CD8 T cell-dependent protective immunity against viral infections. PUBLIC HEALTH RELEVENCE: CD8 T cells play a critical role in defense against several viral infections of humans. In this proposal, we seek to identify key molecular regulators (p27Kip1 and FOXO) that can be modulated in CD8 T cells by immunotherapies to enhance vaccine-induced protective anti-viral immunity. These studies should aid in the development of effective vaccines to protect humans against virally induced diseases.

描述（由申请人提供）：CD8 T 细胞在防御 HIV、乙型和丙型肝炎、EB 病毒、巨细胞病毒和沙粒病毒等病毒感染方面发挥着至关重要的作用。因此，一个主要的推动力是开发新的疫苗接种策略，该策略可以引发有效的 CD8 T 细胞记忆并产生针对这些病毒病原体的有效保护性免疫力。最近的研究表明，记忆 CD8 T 细胞前体作为效应细胞的子集存在于初级 T 细胞反应的高峰期。然而，与有能力的记忆细胞不同，这些记忆前体细胞处于细胞周期停滞状态。它们缺乏通过稳态增殖或响应抗原召回而增殖的自我更新能力，并且提供较差的保护性免疫力。这些记忆前体开始分化程序，通过抗原清除后持续数周的过程成为有能力的记忆细胞。尽管认识到记忆分化的效应子是 CD8 T 细胞依赖性保护性免疫发展的限速步骤，但记忆前体中增殖阻断的诱导和随后逆转的机制尚不清楚。我们使用淋巴细胞脉络膜脑膜炎病毒（LCMV）小鼠模型进行的研究表明，细胞周期蛋白依赖性激酶抑制剂p27Kip1的遗传缺陷不仅加速了记忆细胞与效应CD8 T细胞的分化，而且显着增加了CD8 T细胞记忆的程度。基于这些发现，我们的中心假设是：p27Kip1 通过响应有丝分裂信号而阻止细胞周期重新进入，从而阻碍记忆 CD8 T 细胞与初级效应 CD8 T 细胞的分化。我们进一步假设记忆 CD8 T 细胞分化（包括 p27Kip1 表达）受到上游 FOXO 转录因子的调节。本提案重点通过以下具体目标阐明 FOXO/p27Kip1 通路在调节记忆 CD8 T 细胞分化中的关键作用： 1) 检验 p27Kip1 在调节记忆细胞分化中的作用是 CD8 T 细胞自主的假设 2) 检验 FOXO 转录因子调节记忆 CD8 T 细胞分化的假设。目标 1 和 2 将利用互补方法，包括 TCR 转基因 (tg) 小鼠、骨髓嵌合体、T 细胞中条件性缺乏 p27Kip1 或 FOXO 的小鼠以及可诱导的 p27Kip1/FOXO tg 小鼠，以确定 p27Kip1 和 FOXO 在调节 CD8 T 细胞中发生的表型和功能修饰动态方面的体内作用 从效应细胞分化为有能力的记忆细胞的过程中。这些研究将为控制记忆细胞分化的机制提供重要的见解，并且还有可能将 p27Kip1 和 FOXO 确定为开发新型免疫疗法的分子靶标，以加速和增强疫苗诱导的 CD8 T 细胞依赖性保护性免疫的诱导，以抵抗病毒感染。公共卫生相关性：CD8 T 细胞在防御人类多种病毒感染方面发挥着关键作用。在本提案中，我们寻求确定关键的分子调节因子（p27Kip1 和 FOXO），这些调节因子可以通过免疫疗法在 CD8 T 细胞中进行调节，以增强疫苗诱导的保护性抗病毒免疫。这些研究应有助于开发有效的疫苗，以保护人类免受病毒引起的疾病的侵害。