Regulation of Apoptosis in Activated Primary T Cells

描述（由申请人提供）：维持T细胞稳态对免疫系统的正常功能至关重要。经胸腺细胞选择后，T细胞进入外周淋巴器官并作为初始细胞维持在那里。当初始T细胞经历抗原驱动的扩张并获得效应功能时，稳态会发生短暂的破坏。然后效应T细胞要么经历凋亡（即在群体水平上收缩），要么存活成为记忆细胞。这个过程是至关重要的：它重置T细胞稳态，促进保护性免疫，并限制自身免疫。虽然凋亡的两种途径（死亡受体和Bcl-2调控）都可以影响T细胞的稳态，但最近的数据表明，在常见γ链细胞因子的动态调控下，Bcl-2调控的途径对体内T细胞的稳态至关重要。Bim是一种非冗余的、促凋亡的含有bh -3的分子，对于限制初始T细胞、效应T细胞和较小程度的记忆T细胞的存活至关重要。然而，效应T细胞存活并进入记忆室的机制尚不清楚。这些知识对于我们在治疗上操纵效应T细胞蜕变为记忆T细胞的能力至关重要。我们发现，随着细胞在激活阶段的转变，抗凋亡的Bcl-2家族成员对对抗Bim至关重要，似乎发生了变化。在初始记忆T细胞和静止记忆T细胞中，Bcl-2对对抗Bim和促进生存至关重要。在Bcl-2减少或缺失的情况下，Mcl-1可能拮抗Bim，但效果不如Bcl-2。总的来说，这些新的初步数据表明，通过Stat5到Bcl-2和/或Mcl-1的细胞因子驱动信号调节效应T细胞对bim介导的死亡的易感性。该模型的一个可测试的预测是，细胞因子驱动的Bim拮抗剂应该驱动效应T细胞存活并增强病原体清除。本提案中的实验将测试三个相互关联的假设：(i)当Bcl-2水平低时，Mcl-1在效应T细胞中拮抗Bim； （ii）根据细胞因子环境，Stat5向Bcl-2和/或Mcl-1发出的信号对效应T细胞在体内的存活至关重要；（iii）细胞因子可用性的增强可导致效应T细胞存活和病原体清除的增加。这项研究的长期目标是确定分子靶点，这些靶点可以用于提高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）。公共卫生相关性：维持T细胞稳态对免疫系统的正常功能至关重要。感染后，大多数抵抗感染的T细胞死亡，而一些留下来，成为“记忆”细胞，并提供防止再次感染的保护。控制这些T细胞死亡/存活的机制尚不清楚，但对我们理解保护性免疫至关重要。我们发现单个分子Bim限制了小鼠记忆T细胞的数量。本研究探讨了T细胞正常对抗Bim的机制，以及如何操纵T细胞对抗Bim以提高免疫记忆。

DESCRIPTION (provided by applicant): 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 naive cells. Transient disruption of homeostasis occurs when naive 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 naive, 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 naive 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). PUBLIC HEALTH RELEVANCE: Maintenance of T cell homeostasis is critical for normal functioning of the immune system. After an infection, the majority of T cells that have fought the infection die, while some remain, become "memory" cells, and provide protection from re-infection. Mechanisms that control the death/survival of these T cells remain unclear, but are critical to our understanding of protective immunity. We have found that a single molecule Bim limits the numbers of memory T cells in mice. This proposal explores mechanism(s) by which T cells normally combat Bim and how they can be manipulated to combat Bim to improve immunologic memory.