BcI-2 family in T lymphocyte homeostasis

Bcl-2 家族在 T 淋巴细胞稳态中的作用

• 批准号: 8196843
• 负责人: You-Wen He
• 金额: $ 38.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196843
• 关键词: Address; Animal Model; Animals; Antigens; Apoptosis; Apoptotic; Autophagocytosis; Birth; Cell Death; Cell Survival; Cessation of life; Embryonic Development; Family; Family member; Funding; Genes; Health; Homeostasis; Immune response; Infection; Lead; Left; Ligands; Link; Listeria monocytogenes; Maintenance; Mediating; Memory; Mitochondria; Modeling; Mus; Noxae; Pathway interactions; Peptide/MHC Complex; Permeability; Play; Population; Production; Proteins; Puma; Receptor Signaling; Research; Role; Signal Transduction; Subgroup; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Vaccine Design; cytokine; cytotoxic; in vivo; insight; member; microbial; mouse model; novel; pathogen

DESCRIPTION (provided by applicant): The homeostasis of naive, effector, and memory T lymphocytes is regulated by cytokines, MHC/peptide ligands, and apoptotic pathways. Proteins belonging to the Bcl-2 family are the major players of the intrinsic apoptotic pathway. Recent studies on the role of the Bcl-2 family in T cell apoptosis suggest that members of this family are the principal regulators of the survival/death pathways that decide the fate of T cells. However, most of the studies have focused on pro-apoptotic BH3-only and multi-domain members, leaving the roles of the anti-apoptotic members (Bcl-2, Bcl-xL, Mcl-1, and A1) in regulating the survival of naive, effector, and memory T lymphocytes largely unknown. This is partly due to a lack of appropriate in vivo animal models. For example, mice lacking Bcl-xL and Mcl-1 die embryonically. Mice lacking Bcl-2 die within 3 weeks of birth, precluding the use of these animals to examine T cell immune response in the context of pathogenic infections. We have generated mice conditionally lacking Bcl-x, Bcl-2, and Mcl-1 in T lymphocytes. In addition, we have also generated mice in which Bcl-2 expression is genetically marked. These animal models enable us to address the roles of these anti-apoptotic molecules in regulating the survival of naive, effector, and memory T lymphocytes in vivo using Listeria monocytogenes infection model. Our overall hypothesis is that Bcl-2 and Mcl-1 differentially regulate T cell survival. We propose that on one hand, Bcl-2 primarily promotes the survival of memory T cells, while Mcl-1 is required for the survival of activated/effector T cells. On the other hand, we propose that both Bcl-2 and Mcl-1 promote naive T cell survival, but through distinct mechanisms. To test the above hypothesis, we propose three specific aims: 1: To examine the role of Bcl-2 and Mcl-1 in memory T lymphocyte development. 2: To elucidate the mechanisms by which Mcl-1 protects activated T cells from death. 3: To establish the mechanisms by which Bcl-2 and Mcl-1 protect naive T cells from death. Results from our proposed research will not only establish the roles of these important anti-apoptotic proteins in T cell survival, but also provide novel insights into boosting effector and memory T cell response to microbial pathogens by enhancing their survival. PUBLIC HEALTH RELEVANCE: We propose to study how T cell homeostasis is regulated by anti-apoptotic proteins. The results from this study, if funded, will provide information important in designing vaccines to boost immune response to microbial pathogens.

描述（由申请人提供）：初始、效应和记忆T淋巴细胞的稳态受细胞因子、MHC/肽配体和凋亡途径调节。属于Bcl-2家族的蛋白质是内在凋亡途径的主要参与者。Bcl-2家族在T细胞凋亡中的作用的最新研究表明，该家族的成员是决定T细胞命运的生存/死亡途径的主要调节剂。然而，大多数研究都集中在促凋亡的BH 3-唯一的和多结构域的成员，留下的作用，抗凋亡的成员（Bcl-2，Bcl-xL，Mcl-1，和A1）在调节幼稚，效应和记忆T淋巴细胞的生存在很大程度上未知。这部分是由于缺乏适当的体内动物模型。例如，缺乏Bcl-xL和Mcl-1的小鼠胚胎死亡。缺乏Bcl-2的小鼠在出生后3周内死亡，排除了使用这些动物来检查病原性感染背景下的T细胞免疫应答。我们已经产生了T淋巴细胞中条件性缺乏Bcl-x、Bcl-2和Mcl-1的小鼠。此外，我们还产生了Bcl-2表达被遗传标记的小鼠。这些动物模型使我们能够使用单核细胞增生李斯特菌感染模型来解决这些抗凋亡分子在体内调节幼稚、效应和记忆T淋巴细胞存活中的作用。我们的总体假设是Bcl-2和Mcl-1差异调节T细胞存活。我们提出，一方面，Bcl-2主要促进记忆T细胞的存活，而Mcl-1是活化/效应T细胞存活所必需的。另一方面，我们提出Bcl-2和Mcl-1都促进幼稚T细胞存活，但通过不同的机制。为了验证上述假设，我们提出了三个具体的目标：1：研究Bcl-2和Mcl-1在记忆T淋巴细胞发育中的作用。2.阐明Mcl-1保护活化T细胞免于死亡的机制。3.建立Bcl-2和Mcl-1保护幼稚T细胞免于死亡的机制。我们提出的研究结果不仅将确定这些重要的抗凋亡蛋白在T细胞存活中的作用，而且还将通过增强其存活来增强效应和记忆T细胞对微生物病原体的反应提供新的见解。公共卫生相关性：我们建议研究T细胞的稳态是如何通过抗凋亡蛋白调节的。这项研究的结果如果得到资助，将为设计疫苗以增强对微生物病原体的免疫反应提供重要信息。