Regulation of Apoptosis in Activated Primary T cells

描述(由申请人提供)：维持T细胞稳态对于适应性免疫系统的正常运作至关重要。尽管T细胞动态平衡最终是通过维持不同的T细胞群(幼稚、效应、记忆)来实现的，但在每个种群中维持动态平衡的机制尚不清楚。尽管IL-7对体内T细胞在上述各个阶段的存活至关重要，但人们对控制不同T细胞群体的动态平衡的下游生存机制知之甚少。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至少部分通过改变不同人群中T细胞的存活来调节T细胞的稳态。BCL-2对幼稚T细胞的存活至关重要，至少在一定程度上可以抵消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IL-7Rpha和Bcl2的水平降低，使它们容易受到Bim促凋亡的影响。在没有Bim的情况下，一种特定类型的病毒特异性记忆T细胞的数量在功能和表型上都会增加。这些数据表明，BIM的作用是限制可以进入记忆隔间的效应器T细胞的数量。然而，并不是所有的记忆T细胞都受到影响，记忆T细胞的长期生存可能不需要Bim或Bcl-2。综上所述，这些数据表明，宿主内独立的T细胞群体的维持是由它们对凋亡/生存分子的不同依赖控制的。这一建议的中心假设是，从幼稚到记忆T区的进展涉及到特定阶段对Bim和Bcl2之间的动态平衡的依赖，这种平衡影响依赖于IL-7的幼稚、效应器和效应器T细胞的存活，但不影响中央记忆性T细胞的存活。该项目的目的是确定Bim和Bcl2在以下方面的作用：1.初始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反应)。

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).