Autophagy in T lymphocyte function

T 淋巴细胞功能中的自噬

• 批准号: 7812172
• 负责人: You-Wen He
• 金额: $ 38.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812172
• 关键词: Aging; Autoimmune Diseases; Autophagocytosis; Autophagosome; Catabolic Process; Cell Cycle Progression; Cell Death; Cell Survival; Cell physiology; Cessation of life; Cytosol; Data; Defect; Development; Eukaryotic Cell; Funding; Future; Genes; Homeostasis; Immune response; Infection; Lymphocyte Function; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Membrane; Mitochondria; Molecular; Nerve Degeneration; Organelles; Pathologic Processes; Physiological; Play; Process; Role; Staging; Structure; T-Cell Proliferation; T-Lymphocyte; Testing; Vaccine Design; Vesicle; Work; design; disorder prevention; insight; microbial; novel; pathogen; public health relevance; tumor

DESCRIPTION (provided by applicant): Macroautophagy (hereafter referred to as "autophagy") is a well-conserved catabolic process in eukaryotic cells. It is defined by the formation of double membrane autophagosome vesicles and functions in the intracellular degradation of cytosol and organelles. Although autophagy has long been recognized, its functions in various physiological and pathological processes have only begun to be elucidated. Our recent work has demonstrated that primary T lymphocytes have the capacity to undergo autophagy and that the autophagy gene Atg5 is essential for T cell survival and proliferation, suggesting that autophagy is a novel mechanism regulating mature T cell homeostasis. However, the underlying molecular mechanisms by which autophagy promotes T lymphocyte survival and proliferation remain unknown. Specifically, it is not clear whether the defect in Atg5-/- T cells is caused by an inability to form autophagosomes or an autophagy-independent function of Atg5? More importantly, if impaired autophagy compromises T cell survival, by what mechanism does autophagy inhibit death in T lymphocytes? Using conditional deletion of a second autophagy gene, Atg7, in T lymphocytes, we have established an essential role for autophagy in the survival of naive T lymphocytes. We have found that mitochondrial homeostasis is disrupted in T cells lacking Atg5 or Atg7. These results suggest that autophagy plays a key role in T cell function through maintaining the homeostasis of intracellular organelles. Our overall hypothesis is that autophagic function in mature primary T lymphocytes is required for cell survival and TCR-mediated proliferation through maintaining turnover of cytoplasmic material, in particular the essential organelle structures such as mitochondria. We proposed three specific aims to test this hypothesis. In aim 1, we will determine how autophagy is regulated in primary T lymphocytes and the developmental stages at which the induction of autophagy contributes to cell survival. In aim 2, we will examine how deregulation of organelle homeostasis contributes to cell death in autophagy-deficient primary T lymphocytes. In aim 3, we will establish the mechanisms by which loss of autophagy genes inhibits cell cycle progression during T cell proliferation. Results from this study will shed important insights to the molecular mechanisms by which mature T cell function is regulated. Better understanding this process will undoubtedly help future design of strategies boosting T cell immune responses to pathogens. PUBLIC HEALTH RELEVANCE: We propose to study the roles of an essential intracellular process termed autophagy in regulating T lymphocyte survival and proliferation. The results from this study, if funded, will provide important information for the treatment and prevention of diseases related to T lymphocytes including designing vaccines to boost T cell immune response to microbial pathogens, tumor genesis and autoimmune disease development.

描述（由申请人提供）：大型噬菌体（以下称为“自噬”）是真核细胞中保存良好的分解代谢过程。它是由双膜自噬体囊泡的形成以及在细胞内降解细胞质和细胞器中的功能的定义。尽管长期以来已经认识到自噬，但其在各种生理和病理过程中的功能才开始阐明。我们最近的工作表明，原发性T淋巴细胞具有进行自噬的能力，并且自噬基因ATG5对于T细胞的存活和增殖至关重要，这表明自噬是调节成熟T细胞稳态的新型机制。然而，自噬促进淋巴细胞存活和增殖的潜在分子机制仍然未知。具体而言，尚不清楚ATG5 - / - T细胞中的缺陷是由于无法形成自噬体或ATG5的自噬函数引起的吗？更重要的是，如果自噬受损会损害T细胞的存活，那么自噬会抑制T淋巴细胞死亡的哪种机制？在T淋巴细胞中，使用第二个自噬基因ATG7的条件缺失，我们在幼稚T淋巴细胞生存中确立了自噬的重要作用。我们发现线粒体稳态在缺乏ATG5或ATG7的T细胞中被破坏。这些结果表明，通过维持细胞内细胞器的稳态，自噬在T细胞功能中起关键作用。我们的总体假设是，通过维持细胞质材料的周转，尤其是基本的细胞器结构，例如线粒体，需要进行成熟原发性T淋巴细胞的自噬功能才能进行细胞存活和TCR介导的增殖。我们提出了三个特定的目的来检验这一假设。在AIM 1中，我们将确定在原发性T淋巴细胞中如何调节自噬以及自噬诱导有助于细胞存活的发育阶段。在AIM 2中，我们将研究细胞器稳态的失调如何促进自噬的原发性T淋巴细胞的细胞死亡。在AIM 3中，我们将确定自噬基因损失抑制T细胞增殖过程中细胞周期进程的机制。这项研究的结果将对调节成熟T细胞功能的分子机制提供重要的见解。更好地了解这一过程将无疑有助于未来的设计策略，从而增强对病原体的T细胞免疫反应。公共卫生相关性：我们建议研究一种基本的细胞内过程，该过程称为自噬在调节T淋巴细胞生存和增殖中的作用。这项研究的结果（如果资助）将提供重要信息，以治疗和预防与T淋巴细胞有关的疾病，包括设计疫苗以增强对微生物病原体，肿瘤起源和自身免疫性疾病发展的T细胞免疫反应。