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 淋巴细胞的稳态受细胞因子、MHC/肽配体和凋亡途径调节。 Bcl-2 家族的蛋白质是内在凋亡途径的主要参与者。最近关于 Bcl-2 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促凋亡 BH3 和多结构域成员上，而抗凋亡成员（Bcl-2、Bcl-xL、Mcl-1 和 A1）在调节初始 T 淋巴细胞、效应 T 淋巴细胞和记忆 T 淋巴细胞的存活中的作用很大程度上未知。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 的小鼠在胚胎时期就会死亡。缺乏 Bcl-2 的小鼠在出生后 3 周内死亡，因此无法使用这些动物来检查病原体感染情况下的 T 细胞免疫反应。我们培育了 T 淋巴细胞中有条件地缺乏 Bcl-x、Bcl-2 和 Mcl-1 的小鼠。此外，我们还培育了 Bcl-2 表达具有基因标记的小鼠。这些动物模型使我们能够利用单核细胞增生李斯特氏菌感染模型来阐明这些抗凋亡分子在调节体内幼稚、效应和记忆T淋巴细胞的存活中的作用。我们的总体假设是 Bcl-2 和 Mcl-1 差异性地调节 T 细胞存活。我们认为，一方面，Bcl-2 主要促进记忆 T 细胞的存活，而 Mcl-1 是激活/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 细胞的存活，但通过不同的机制。为了检验上述假设，我们提出三个具体目标： 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 T 细胞免于死亡的机制。图 3：建立 Bcl-2 和 Mcl-1 保护初始 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，而且还将为通过增强效应和记忆 T 细胞的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。

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.