BcI-2 family in T lymphocyte homeostasis

Bcl-2 家族在 T 淋巴细胞稳态中的作用

基本信息

批准号：
8389558
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2014-11-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：幼稚，效应子和记忆T淋巴细胞的稳态受细胞因子，MHC/肽配体和凋亡途径的调节。属于Bcl-2家族的蛋白质是内在凋亡途径的主要参与者。关于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BH3-且多域成员上，留下了抗凋亡成员（Bcl-2，Bcl-XL，MCL-1和A1）在调节天真，效应和记忆型淋巴细胞生存中的生存中的作用。这部分是由于缺乏合适的体内动物模型。例如，缺乏BCL-XL和MCL-1的小鼠胚胎死亡。缺乏Bcl-2的小鼠在出生后的3周内死亡，从而排除了这些动物在致病性感染的背景下检查T细胞免疫反应。我们已经在T淋巴细胞中有条件地产生了有条件缺乏Bcl-X，Bcl-2和Mcl-1的小鼠。此外，我们还产生了Bcl-2表达在遗传上标记的小鼠。这些动物模型使我们能够通过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，效应子和记忆T淋巴细胞生存的作用。我们的总体假设是Bcl-2和Mcl-1差异调节T细胞的存活。我们建议一方面BCL-2主要促进记忆T细胞的存活，而MCL-1则是激活/效应T细胞存活所必需的。另一方面，我们建议Bcl-2和Mcl-1都可以通过不同的机制促进幼稚的T细胞存活。为了检验上述假设，我们提出了三个具体目的：1：检查Bcl-2和MCl-1在记忆T淋巴细胞发育中的作用。 2：阐明MCL-1保护活化的T细胞免受死亡的机制。 3：建立Bcl-2和Mcl-1保护幼稚T细胞免受死亡的机制。我们提出的研究的结果不仅将在T细胞存活中确定这些重要的抗凋亡蛋白的作用，而且还可以通过增强其存活率来增强效应子和对微生物病原体的记忆T细胞反应的新颖见解。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection.

DOI：
10.1038/srep06359
发表时间：
2014-09-15
期刊：
Scientific reports
影响因子：
4.6
作者：
Chen CF;Feng X;Liao HY;Jin WJ;Zhang J;Wang Y;Gong LL;Liu JJ;Yuan XH;Zhao BB;Zhang D;Chen GF;Wan Y;Guo J;Yan HP;He YW
通讯作者：
He YW

Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes.