Regulation of Apoptosis in Activated Primary T cells

描述（由申请人提供）：T细胞稳态的维持对于适应性免疫系统的正常功能至关重要。虽然T细胞稳态最终是通过维持不同的T细胞群体（幼稚、效应、记忆）来实现的，但在每个群体中维持稳态的机制尚不清楚。虽然IL-7在这些阶段中的每一个对于T细胞在体内的存活是至关重要的，但是对于控制不同T细胞群体的稳态的下游存活机制知之甚少。我们的初步数据表明，抗凋亡分子Bim及其抗凋亡拮抗剂Bcl-2调节T细胞稳态，至少部分通过改变T细胞在不同人群中的存活。Bcl-2对于幼稚T细胞存活是至关重要的，至少部分地抵消Bim的促凋亡作用。在病毒特异性效应T细胞中，大多数病毒特异性T细胞上的IL-7 Ra和Bcl-2水平降低，使它们对Bim的促凋亡作用敏感。在缺乏Bim的情况下，特定类型的病毒特异性记忆T细胞的数量在功能上和表型上都增加。这些数据表明Bim的作用是限制可以进入记忆区的效应T细胞的数量。然而，并非所有的记忆T细胞都受到影响，记忆T细胞的长期存活可能不需要Bim或Bcl-2。总之，这些数据表明，在宿主内的T细胞的独立群体的维持是由它们对凋亡/存活分子的不同依赖性控制的。该提议的中心假设是，从幼稚T隔室到记忆T隔室的进展涉及对Bim和Bcl-2之间的动态平衡的阶段特异性依赖，该平衡影响幼稚T细胞、效应T细胞和效应记忆T细胞的IL-7依赖性存活，但不影响中央记忆T细胞。该项目的目的是确定Bim和Bcl-2在以下方面的作用：1.幼稚T细胞稳态; 2.效应T细胞凋亡; 3.记忆T细胞存活和表型。这项研究的长期目标是确定可用于治疗的分子靶点，以提高T细胞存活率（即改善疫苗接种）或降低T细胞存活率（即抑制自身免疫性疾病或移植排斥）。

DESCRIPTION (provided by applicant): Maintenance of T cell homeostasis is critical for normal functioning of the adaptive immune system. Although T cell homeostasis is ultimately achieved through maintenance of distinct T cell populations (naive, effector, memory), the mechanisms by which homeostasis is maintained in each population is unclear. Although IL-7 is critical for survival of T cells in vivo at each of these stages, little is known about the downstream survival mechanisms by which homeostasis of distinct T cell populations are controlled. Our preliminary data indicate that the anti-apoptotic molecule, Bim and its anti-apoptotic antagonist, Bcl-2, regulate T cell homeostasis, at least in part by altering T cell survival in distinct populations. Bcl-2 is critical for naive T cell survival, at least in part, to counteract the pro-apoptotic effects of Bim. In viral-specific effector T cells, levels of IL-7Ralpha and Bcl-2 are decreased on most viral-specific T cells, leaving them susceptible to the pro-apoptotic effects of Bim. In the absence of Bim the numbers of a particular type of viral-specific memory T cell are increased, both functionally and phenotypically. These data suggest that the role of Bim is to limit the numbers of effector T cells that can enter the memory compartment. However, not all memory T cells are affected and the long-term survival of memory T cells may not require Bim or Bcl-2. Taken together, these data suggest that the maintenance of independent populations of T cells within the host is controlled by their different dependence on apoptosis/survival molecules. The central hypothesis of this proposal is that progression from naive to memory T compartments Involves stage-specific dependence on a dynamic balance between Bim and Bcl-2, a balance that affects IL-7-dependent survival of naive, effector, and effector memory but not central memory T cells. The aims of the project are to determine the roles of Bim and Bcl-2 in : 1. naive T cell homeostasis; 2. effector T cell apoptosis; 3. memory T cell survival and phenotype. The long-term goal of this research is to identify molecular targets that could be exploited therapeutically to enhance T cell survival (i.e. to improve vaccination) or to decrease T cell survival (i.e. suppress autoimmune disease or transplant rejection).