REGULATION OF APOPTOSIS IN THYMOCYTES

T淋巴细胞群体区分“自我”的能力 而“非我”是免疫系统的中心特征。 自身MHC限制性T细胞克隆的阳性选择和阴性 自体反应性T细胞克隆的选择发生在胸腺中，并在 胸腺细胞亚群CD48TCR/CD3的不同发育阶段。 积极选择似乎涉及自体MHC限制性的拯救 来自预先编程的细胞死亡过程的细胞，称为细胞凋亡 相反，负选择似乎涉及到重新激活或 重新诱导先前被拯救的细胞的凋亡 在积极选择的过程中。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 防止胸腺细胞凋亡。这种保护机制的激活 因此可能对正向选择及其失活至关重要 对于负面选择可能是至关重要的。因此，对两种细胞凋亡的分析 而对细胞凋亡的保护可以作为一个模型来研究 T细胞谱系选择的调控。 该项目有三个具体目标，提出以下问题： 1.TCR信号如何调控细胞凋亡及保护作用 那么消极选择呢？ 2.非TCR信号如何调控细胞凋亡和保护 积极选择和消极选择？ 3.胸腺内的CD4配体是什么，它调节着 未成熟胸腺细胞对TCR参与的反应？ 这些研究应该有助于更好地理解积极和 免疫系统中的负面选择，因此可以促进 旨在调节淋巴生长和发育的临床策略， 例如针对抗肿瘤反应的抗原特异性疗法， 移植排斥和自身免疫反应，因为在每一个 在这些情况下，“不适当的”T细胞谱系是导致 临床困难。

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.