Mechanisms of CD8 T Cell Apoptosis

该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的缺失有关 CDS T细胞。重要的是，通过病毒感染或接触类Toll激活天然免疫 受体激动剂可以阻止同种异体反应性CDS T细胞的缺失和耐受诱导。具体的 本研究的重点是明确CDS T细胞凋亡的分子机制。 我们建议研究CDS T细胞死亡的生化机制(特定目标1)。这些 这些研究将为CD8 T细胞死亡特定途径的分子研究提供基础 (具体目标2和3)。已经证实，Bcl2蛋白家族的成员起着关键的调节作用 CDS T细胞死亡。此外，应激激活蛋白激酶家族的成员参与了 CDS T细胞死亡的规律。我们将在移植诱导过程中检查这些途径。 联合仿真封锁期间的容忍度。我们还将检查CDB T细胞在移植时的死亡情况 接触Toll样受体激动剂和淋巴细胞性脉络膜脑膜炎病毒可破坏耐受性 (LCMV)感染。这些研究完全结合在方案项目的主题中，并依赖于 基于与其他项目的合作研究。 这项建议的具体目的是研究： 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.Bcl2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为 对移植耐受性的理解以及我们获得的新信息将有助于 治疗人类疾病的疗法的设计。

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.