CD8 Mediated Apoptosis During T Cell Development

T 细胞发育过程中 CD8 介导的细胞凋亡

• 批准号: 7320666
• 负责人: TERRY A POTTER
• 金额: $ 31.73万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320666
• 关键词: Antibodies; Antigen-Presenting Cells; Apoptosis; Binding; Biochemical; CD3 Antigens; CD8B1 gene; Cessation of life; Condition; Event; Histocompatibility Antigens Class I; Induction of Apoptosis; Ligation; MHC Class I Genes; Mediating; Modeling; Monitor; Movement; Peripheral; Phorbol Esters; Physiological; Population; Proteins; Role; System; T-Cell Development; T-Lymphocyte; Tetradecanoylphorbol Acetate; crosslink; follow-up; human prostaglandin D2 receptor; immunological synapse; neglect; prevent; receptor; thymocyte

DESCRIPTION (provided by applicant): During the interaction of T cells with antigen presenting cells (APCs), receptors and intracellular proteins translocate into the contact region known as the Immunological Synapse (IS). In the first Aim we will examine whether CD8 behaves as a coreceptor within the immunological synapse, for the activation of peripheral T cells. In the other component of this proposal we shall follow up on our recent observation that cross-linking of CD8, but not CD4, with antibodies or MHC class I molecules, results in rapid apoptosis of CD4+CD8+ (DP) thymocytes. We have identified the thymocytes that are susceptible to this CD8 mediated apoptosis as an early DP population that expresses low levels of CD2 and CD5 and is CD69-. Treatment with the phorbol ester, PMA, or antibodies to CD3, prevents this induction of apoptosis. We hypothesize that ligation of CD8 by MHC class I molecules in the absence of TCR engagement leads to the death of a subpopulation of early DP thymocytes. Furthermore, our system may provide a model for thymocytes that fail positive selection and are said to undergo "death by neglect". In this proposal we shall further characterize the induction of apoptosis in DP thymocytes by CD8 antibodies and MHC class I molecules according to 3 specific aims: (i) to determine the biochemical events leading to the CD8 mediated death of DP thymocytes; (ii) to determine the mechanism by which treatment with PMA, or engagement of the TCR, prevents CD8 mediated death in DP thymocytes; (iii) to determine whether CD8 mediated death functions under physiological conditions.

描述（由申请人提供）：在 T 细胞与抗原呈递细胞 (APC) 相互作用的过程中，受体和细胞内蛋白质易位到称为免疫突触 (IS) 的接触区域。在第一个目标中，我们将检查 CD8 是否充当免疫突触内的辅助受体，用于激活外周 T 细胞。 在该提案的其他部分中，我们将跟进我们最近的观察结果，即 CD8（而非 CD4）与抗体或 MHC I 类分子的交联会导致 CD4+CD8+ (DP) 胸腺细胞快速凋亡。我们已经鉴定出对这种 CD8 介导的细胞凋亡敏感的胸腺细胞作为早期 DP 群体，表达低水平的 CD2 和 CD5，并且是 CD69-。用佛波酯、PMA 或 CD3 抗体治疗可防止诱导细胞凋亡。我们假设在没有 TCR 参与的情况下，MHC I 类分子连接 CD8 会导致早期 DP 胸腺细胞亚群的死亡。此外，我们的系统可以为未通过正选择并据说经历“忽视死亡”的胸腺细胞提供模型。 在本提案中，我们将根据 3 个具体目标进一步描述 CD8 抗体和 MHC I 类分子诱导 DP 胸腺细胞凋亡的特征：（i）确定导致 CD8 介导的 DP 胸腺细胞死亡的生化事件； (ii) 确定 PMA 治疗或 TCR 参与预防 DP 胸腺细胞中 CD8 介导的死亡的机制； (iii)确定CD8在生理条件下是否介导死亡功能。