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: 7154097
• 负责人: TERRY A POTTER
• 金额: $ 32.34万
• 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/7154097
• 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）相互作用期间，受体和细胞内蛋白质移位到称为免疫突触（IS）的接触区域。在第一个目标中，我们将研究CD 8是否作为免疫突触内的辅助受体，用于激活外周T细胞。 在本提案的另一部分中，我们将继续我们最近的观察，即CD 8，而不是CD 4，与抗体或MHC I类分子的交联，导致CD 4 + CD 8+（DP）胸腺细胞的快速凋亡。我们已经确定了胸腺细胞，这是敏感的CD 8介导的细胞凋亡作为一个早期DP人口表达低水平的CD 2和CD 5和CD 69-。用佛波醇酯、PMA或CD 3抗体治疗可防止这种凋亡诱导。我们推测，在没有TCR参与的情况下，MHC I类分子与CD 8的连接导致早期DP胸腺细胞亚群的死亡。此外，我们的系统可以提供一个模型的胸腺细胞，失败的积极选择，据说经历“死亡的忽视”。 在这个提议中，我们将根据3个特定目的进一步表征由CD 8抗体和MHC I类分子诱导DP胸腺细胞凋亡：（i）确定导致DP胸腺细胞的CD 8介导的死亡的生化事件;（ii）确定用PMA处理或TCR的参与防止DP胸腺细胞中的CD 8介导的死亡的机制;（iii）确定CD 8介导的死亡是否在生理条件下起作用。