Mechanisms of CD8 T Cell Apoptosis

本研究计划的总体目标是了解共刺激介导的移植耐受 封锁这种形式的移植耐受与同种异体反应性T细胞的缺失有关。 CDS T细胞。重要的是，通过病毒感染或暴露于Toll样抗原激活先天免疫， 受体激动剂可以阻止同种异体反应性CD8 T细胞的缺失和耐受诱导。具体 本研究的重点是明确CDS T细胞凋亡的分子机制。 我们建议检查CDS T细胞死亡的生化机制（特异性目的1）。这些 这些研究将为CD8 T细胞死亡的特定途径的分子研究提供基础 （具体目标2和3）。已经确定Bcl 2蛋白家族的成员作为细胞凋亡的关键调节因子， CDS T细胞死亡。此外，应激活化蛋白激酶家族成员也参与了 CDS T细胞死亡的调节。我们将在移植诱导过程中检查这些通路 共刺激阻断期间的耐受性。我们还将检查移植时CDB T细胞的死亡情况。 暴露于Toll样受体激动剂和淋巴细胞性脉络丛脑膜炎病毒可破坏耐受性 （LCMV）感染。这些研究完全融入方案项目的主题，并取决于 与其他项目合作研究。 该提案的具体目标是审查： 1. CDS T细胞死亡的生化机制。 2.应激激活的MAP激酶在CDS T细胞死亡中的作用。 3. Bcl 2家族蛋白在CDB T细胞死亡中的作用。 我们预计，这些研究的成功完成将提供重要的新的见解， 对移植耐受性的理解，我们获得的新信息将有助于 设计治疗人类疾病的疗法。

The overall goal of this research program is to understand transplantation tolerance mediated by costimulation blockade. This form of transplantation tolerance is associated with the deletion of alloreactive CDS T cells. Importantly, the activafion of innate immunity by virus infection or exposure to Toll-like receptor agonists can prevent both alloreactive CDS T cell delefion and tolerance induction. The specific focus of this Study is to define the molecular mechanisms of CDS T cell apoptosis. We propose to examine the biochemical mechanism of CDS T cell death (Specific Aim 1). These Studies will provide the foundation for molecular studies of specific pathways of CD8 T cell death (Specific Aims 2 & 3). It is established that members of the Bcl2 protein family act as critical regulators of CDS T cell death. Moreover, members ofthe stress-activated protein kinase family are implicated in the regulafion of CDS T cell death. We will examine these pathways during the induction of transplantation tolerance during co-sfimulation blockade. We will also examine CDB T cell death when transplantafion tolerance is disrupted by exposure to Toll-like receptor agonists and lymphocyfic choriomeningifis virus (LCMV) infection. These studies are fully integrated within the theme of the Program Project and depend upon collaborative studies with the other Projects. The Specific Aims of this proposal are to examine the: 1. Biochemical mechanism of CDS T cell death. 2. Role of stress-activated MAP kinases in CDS T cell death. 3. Role of Bcl2 familv proteins in CDB T cell death. We anticipate that the successful completion of these studies will provide important new insight into the understanding of transplantafion tolerance and that the new informafion we obtain will contribute to the design of therapies for the treatment of human disease.