REGULATION OF APOPTOSIS IN THYMOCYTES

胸腺细胞凋亡的调节

• 批准号: 2067447
• 负责人: Susan A. McCarthy
• 金额: $ 9.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2067447
• 关键词: CD3 molecule; CD4 molecule; T cell receptor; T lymphocyte; apoptosis; autoimmunity; biological signal transduction; gene expression; hamsters; laboratory mouse; leukocyte activation /transformation; monoclonal antibody; northern blottings; polymerase chain reaction; thymus

The ability of the T lymphocyte population to distinguish between "self" and "non-self" is the central characteristic of the immune system. Positive selection of self-MHC-restricted T cell clones, and negative selection of auto-reactive T cell clones occur in the thymus, and operate on distinct developmental stages of the CD4+8+ TcR/CD3+ thymocyte subset. Positive selection appears to involve the rescue of self-MHC-restricted cells from a process of pre-programmed cell death known as apoptosis Negative selection, in contrast, appears to involve the re-activation or re-induction of apoptosis in cells that had previously been rescued during positive selection. An important new component to the regulation of apoptosis in thymocytes is a "protective" mechanism that-can spare thymocytes from apoptosis. The activation of this protective mechanism may therefore be critical for positive selection, and its inactivation may be critical for negative selection. Thus, analysis of both apoptosis and protection from apoptosis can be used as a model to investigate the regulation of T cell repertoire selection. This project has three Specific Aims, asking the following questions: 1. How do TcR signals regulate apoptosis and protection during positive and negative selection? 2. How do non-TcR signals regulate apoptosis and protection during positive and negative selection? 3. What is the intrathymic CD4 ligand that regulates the ability of immature thymocytes to respond to TcR engagement? These studies should contribute to a better understanding of positive and negative selection in the immune system, and could therefore facilitate clinical strategies designed to regulate lymphoid growth and development, such as antigen-specific therapies for anti-tumor responses, transplantation rejection and autoimmune responses, since in each of these cases, an "inappropriate" T cell repertoire is the cause of the clinical difficulty.

T淋巴细胞群区分“自身”的能力 而“非我”是免疫系统的核心特征。 自身MHC限制性T细胞克隆的阳性选择，以及阴性选择。 自身反应性T细胞克隆的选择发生在胸腺中， 在不同发育阶段的CD 4 +8+ TcR/CD 3+胸腺细胞亚群。 积极的选择似乎涉及拯救自我MHC限制性 这是一个被称为细胞凋亡的程序性细胞死亡过程 相反，负选择似乎涉及重新激活或 重新诱导先前被拯救的细胞凋亡 在积极的选择。 该法规的一个重要新组成部分 胸腺细胞的凋亡是一种“保护性”机制， 胸腺细胞凋亡。 这种保护机制的激活 因此可能是正选择的关键， 可能是负选择的关键。 因此，分析细胞凋亡 细胞凋亡的保护作用可以作为研究细胞凋亡的模型。 调节T细胞库选择。 该项目有三个具体目标，提出以下问题： 1. TcR信号如何调节细胞凋亡和保护作用 负选择？ 2.非TcR信号是如何调节细胞凋亡和细胞保护的？ 积极选择和消极选择？ 3.什么是胸腺内CD 4配体，它调节 不成熟的胸腺细胞对TcR结合的反应？ 这些研究应有助于更好地了解积极和 免疫系统中的负选择，因此可以促进 设计用于调节淋巴生长和发育的临床策略， 例如用于抗肿瘤反应的抗原特异性疗法， 移植排斥反应和自身免疫反应，因为在每一个 在这些情况下，“不适当的”T细胞库是导致 临床困难