BcI-2 family in T lymphocyte homeostasis

描述(由申请人提供)：幼稚T淋巴细胞、效应T淋巴细胞和记忆T淋巴细胞的动态平衡受细胞因子、MHC/多肽配体和凋亡途径的调节。属于Bcl2家族的蛋白质是固有的细胞凋亡途径的主要参与者。最近关于Bcl2家族在T细胞凋亡中的作用的研究表明，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者。然而，大多数研究都集中在BH3单功能域和多结构域成员上，而对抗凋亡成员(Bcl2、Bclxl、Mcl-1和A1)在调节幼稚T细胞、效应T细胞和记忆T细胞存活中的作用还知之甚少。这在一定程度上是由于缺乏合适的活体动物模型。例如，缺乏Bcl-xl和Mcl-1的小鼠会在胚胎中死亡。缺乏Bcl-2的小鼠在出生后3周内死亡，这排除了使用这些动物在病原性感染背景下检查T细胞免疫反应的可能性。我们已经产生了T淋巴细胞中有条件地缺乏Bclx、Bcl2和Mcl-1的小鼠。此外，我们还培育了带有基因标记的Bcl2基因表达的小鼠。这些动物模型使我们能够利用单核细胞增多性李斯特氏菌感染模型来研究这些抗凋亡分子在体内调节幼稚T细胞、效应T细胞和记忆T细胞存活的作用。我们的总体假设是，Bcl-2和Mcl-1以不同的方式调节T细胞的存活。我们认为，一方面，Bcl2主要促进记忆T细胞的存活，而Mcl-1是激活/效应T细胞生存所必需的。另一方面，我们认为Bcl-2和Mcl-1都促进了初始T细胞的存活，但机制不同。为了验证上述假设，我们提出了三个具体的目标：1：研究Bcl2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，而且还将为通过提高T细胞对微生物病原体的存活来增强效应和记忆T细胞的反应提供新的见解。公共卫生相关性：我们建议研究T细胞稳态是如何由抗凋亡蛋白调节的。这项研究的结果，如果得到资助，将为设计疫苗以提高对微生物病原体的免疫反应提供重要信息。

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.