Autophagy in T lymphocyte function

T 淋巴细胞功能中的自噬

• 批准号: 8461210
• 负责人: You-Wen He
• 金额: $ 35.93万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461210
• 关键词: Aging; Autoimmune Diseases; Autophagocytosis; Autophagosome; Catabolic Process; Cell Cycle Progression; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cessation of life; Cytosol; Data; Defect; Development; Eukaryotic Cell; Funding; Future; Genes; Health; Homeostasis; Immune response; Infection; Lymphocyte Function; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Membrane; Mitochondria; Molecular; Nerve Degeneration; Organelles; Pathologic Processes; Physiological Processes; Play; Process; Role; Staging; Structure; T-Cell Proliferation; T-Lymphocyte; Testing; Vaccine Design; Vesicle; Work; design; disorder prevention; insight; microbial; novel; pathogen; 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.

描述（由申请人提供）：巨自噬（以下简称“自噬”）是真核细胞中高度保守的分解代谢过程。它的定义是双层膜自噬体囊泡的形成，并在胞质溶胶和细胞器的细胞内降解中发挥作用。尽管自噬早已被人们认识，但其在各种生理和病理过程中的功能才刚刚开始被阐明。我们最近的工作表明，原代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细胞稳态的新机制。然而，自噬促进 T 淋巴细胞存活和增殖的潜在分子机制仍不清楚。具体来说，尚不清楚Atg5-/- T细胞的缺陷是由于Atg5无法形成自噬体还是自噬独立功能引起的？更重要的是，如果自噬受损会损害 T 细胞的存活，那么自噬通过什么机制抑制 T 淋巴细胞死亡？通过条件性删除 T 淋巴细胞中的第二个自噬基因 Atg7，我们确定了自噬在初始 T 淋巴细胞的存活中的重要作用。我们发现缺乏 Atg5 或 Atg7 的 T 细胞中线粒体稳态被破坏。这些结果表明自噬通过维持细胞内细胞器的稳态在 T 细胞功能中发挥关键作用。我们的总体假设是，成熟原代 T 淋巴细胞中的自噬功能是细胞存活和 TCR 介导的增殖所必需的，通过维持细胞质物质（特别是线粒体等重要细胞器结构）的周转。我们提出了三个具体目标来检验这一假设。在目标 1 中，我们将确定原代 T 淋巴细胞中自噬的调节方式以及自噬诱导有助于细胞存活的发育阶段。在目标 2 中，我们将研究细胞器稳态失调如何导致自噬缺陷的原代 T 淋巴细胞的细胞死亡。在目标 3 中，我们将建立自噬基因缺失抑制 T 细胞增殖过程中细胞周期进程的机制。这项研究的结果将为成熟 T 细胞功能调节的分子机制提供重要的见解。更好地理解这一过程无疑将有助于未来设计增强 T 细胞对病原体免疫反应的策略。

项目成果

The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression.

• DOI: 10.4049/jimmunol.1100710
• 发表时间: 2011-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: McLeod IX;Zhou X;Li QJ;Wang F;He YW
• 通讯作者: He YW

Transfer of CD8+ T cell memory using Bcl-2 as a marker.

• DOI: 10.4049/jimmunol.1103481
• 发表时间: 2013-02-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Dunkle A;Dzhagalov I;Gordy C;He YW
• 通讯作者: He YW

Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.

• DOI: 10.1158/2159-8290.cd-15-1412
• 发表时间: 2016-09
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Wang Y;Sun SN;Liu Q;Yu YY;Guo J;Wang K;Xing BC;Zheng QF;Campa MJ;Patz EF Jr;Li SY;He YW
• 通讯作者: He YW

Regulation of T-cell survival and mitochondrial homeostasis by TSC1.

• DOI: 10.1002/eji.201141411
• 发表时间: 2011-11
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: O'Brien, Thomas F.;Gorentla, Balachandra K.;Xie, Danli;Srivatsan, Sruti;McLeod, Ian X.;He, You-Wen;Zhong, Xiao-Ping
• 通讯作者: Zhong, Xiao-Ping

Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes.

• DOI: 10.4049/jimmunol.1001822
• 发表时间: 2011-02-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Jia W;Pua HH;Li QJ;He YW
• 通讯作者: He YW