Regulation of Apoptosis in Activated Primary T Cells

T细胞动态平衡的维持对于免疫系统的正常运作至关重要。之后 胸腺细胞选择，T细胞进入外周淋巴器官，并作为NA细胞维持在那里。 当NA？VE T细胞经历抗原驱动的扩增和 获取效应器功能。然后效应者T细胞要么经历凋亡(即在群体中收缩 水平)或存活成为存储单元。这个过程是至关重要的：它重置T细胞的动态平衡，促进 保护性免疫，并限制自身免疫力。而细胞凋亡的两条途径(死亡受体和Bcl2 调节的)可以影响T细胞的动态平衡，最近的数据表明在动态的情况下，Bcl2调节的通路 共同的伽马链细胞因子的调节，作为T细胞体内稳态的关键。BIM是一种非 冗余的、含BH-3的促凋亡分子，对限制NA、效应器和 较小范围的记忆T细胞。然而，效应T细胞存活并进入体内的机制(S) 记忆舱仍不清楚。这些知识对于我们的治疗能力至关重要。 操控效应T细胞向记忆T细胞的蜕变。我们发现随着细胞的转变， 经过几个阶段的激活，对于对抗Bim至关重要的抗细胞凋亡的Bcl2家族成员似乎 变化。在NAVE和静息记忆T细胞中，Bcl2在拮抗BIM和促进存活方面起着关键作用。在……里面 在Bcl-2减少或缺失的情况下，Mcl-1可能拮抗Bim，但其作用效率低于 BCL-2。总的来说，这些新的初步数据表明了一个模型，在该模型中，细胞因子通过 Stat5-to Bcl-2和/或Mcl-1调节效应T细胞对Bim介导的死亡的敏感性。一个可测试的 该模型的预测是，细胞因子驱动的BIM拮抗作用应促进效应者T细胞存活和 加强病原体清除。本提案中的实验将检验三个相互关联的假设：(I)Mcl-1 当Bcl2水平较低时拮抗效应T细胞中的Bim(II)依赖于细胞因子环境Stat5 Bcl2和/或Mcl-1信号对体内效应T细胞的存活至关重要；以及(Iii)增强 细胞因子的可获得性可以增加效应者T细胞的存活率和病原体清除。长期的 这项研究的目标是确定可以用于治疗的分子靶点，以增强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)。

Maintenance of T cell homeostasis is critical for normal functioning of the immune system. After thymocyte selection, T cells enter the peripheral lymphoid organs and are maintained there as na¿ve cells. Transient disruption of homeostasis occurs when na¿ve T cells undergo antigen-driven expansion and acquire effector functions. Effector T cells then either undergo apoptosis (i.e., contraction at the population level) or survive to become memory cells. This process is crucial: it resets T cell homeostasis, promotes protective immunity, and limits autoimmunity. While both pathways of apoptosis (death receptor and Bcl-2 regulated) can affect T cell homeostasis, recent data point to the Bcl-2-regulated pathway, under dynamic regulation by common gamma chain cytokines, as being critical for T cell homeostasis in vivo. Bim is a non- redundant, pro-apoptotic BH-3-containing molecule critical for limiting survival of na¿ve, effector, and to a lesser extent memory T cells. However, the mechanism(s) by which effector T cells survive and enter the memory compartment remain unclear. Such knowledge is crucial for our ability to therapeutically manipulate the metamorphosis of effector T cells to memory T cells. We have found that as cells transition through stages of activation, the anti-apoptotic Bcl-2 family members critical for combating Bim appear to change. In na¿ve and resting memory T cells, Bcl-2 is critical to antagonize Bim and promote survival. In situations where Bcl-2 is decreased or absent, Mcl-1 likely antagonizes Bim, but does so less efficiently than Bcl-2. Collectively, these new preliminary data suggest a model in which cytokine-driven signals through Stat5 to Bcl-2 and/or Mcl-1 modulate susceptibility of effector T cells to Bim-mediated death. A testable prediction of this model is that cytokine-driven antagonism of Bim should drive effector T cell survival and enhance pathogen clearance. Experiments in this proposal will test three interrelated hypotheses: (i) Mcl-1 antagonizes Bim in effector T cells when Bcl-2 levels are low (ii) depending upon the cytokine milieu Stat5 signaling to Bcl-2 and/ or Mcl-1 is critical for survival of effector T cells in vivo; and (iii) enhancement of cytokine availability can lead to increased effector T cell survival and pathogen clearance. 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).