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（以下称为“自噬”）是真核细胞中非常保守的分解代谢过程。它通过形成双膜自噬体囊泡来定义，并在胞质溶胶和细胞器的细胞内降解中起作用。虽然自噬早已被认识，但其在各种生理和病理过程中的功能才刚刚开始阐明。我们最近的工作表明，原代T淋巴细胞有能力进行自噬和自噬基因Atg 5是T细胞的生存和增殖所必需的，这表明自噬是一种新的机制，调节成熟的T细胞的稳态。然而，自噬促进T淋巴细胞存活和增殖的潜在分子机制仍然未知。具体来说，目前尚不清楚Atg 5-/- T细胞的缺陷是由无法形成自噬体或Atg 5的自噬独立功能引起的？更重要的是，如果受损的自噬损害T细胞的存活，自噬通过什么机制抑制T淋巴细胞的死亡？在T淋巴细胞中使用第二个自噬基因Atg 7的条件性缺失，我们已经建立了自噬在幼稚T淋巴细胞存活中的重要作用。我们已经发现，线粒体稳态在缺乏Atg 5或Atg 7的T细胞中被破坏。这些结果表明，自噬通过维持细胞内细胞器的稳态在T细胞功能中起关键作用。我们的总体假设是，成熟的原代T淋巴细胞中的自噬功能是细胞存活和TCR介导的增殖所需的，通过维持细胞质物质的周转，特别是基本的细胞器结构，如线粒体。我们提出了三个具体目标来检验这一假设。在目标1中，我们将确定自噬在初级T淋巴细胞中是如何调节的，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的丢失在T细胞增殖期间抑制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