ANTIGEN INDUCED APOPTOSIS (PROPRIOCIDAL REGULATION) OF MATURE T LYMPHOCYTES

这个项目是基于我们的发现，刺激抗原 细胞暴露于有丝分裂后的成熟T细胞受体 IL-2等淋巴因子可诱导细胞程序性死亡 或细胞凋亡(固有的杀伤性调节)。我们感兴趣的是 本体法的调控机制。我们也在研究这是否 机制可以解释某些免疫“抑制”现象 以及这一机制如何在 针对人类疾病的各种免疫调节策略正在尝试之中。 我们已经开始探索具体的方式，即 抗原与受体结合影响是否诱导细胞凋亡。 使用一组不同氨基酸的多肽变体 鸽细胞色素88-104位第99位取代 C，我们已经发现了不会诱导IL-2或其他细胞因子的变体，但 仍然会启动T细胞的凋亡。对两起此类案件的进一步调查 “改变的多肽配体”表明，这些不会引起同样的反应。 CD3链，TCRzeta链， ZAP70激酶为88-104肽。相反，导致死亡的 多肽配体的改变只导致一种形式的TCRzeta磷酸化 以及一种新型的Fyn激酶分子的磷酸化。这些 结果表明，质地不同类型的T细胞受体 参与可能通过不同的信号通路诱导细胞凋亡。 这些发现还表明，某些改变的多肽配体可能 是有效的耐受剂，没有导致T细胞激活的风险，这 可能导致T细胞介导的诱导凋亡治疗的改进 疾病。 我们还仔细研究了半胱氨酸蛋白酶的类型，这些酶是 在本体杀伤性死亡期间诱发的。我们发现CPP32beta和 ICELAP3而不是白介素1β转换酶(ICE)是 在T细胞死亡过程中蛋白水解性激活。这个不同于其他 ICE似乎首先被激活并在其中起作用的细胞类型 CPP32β的激活。我们还发现，特定的抑制因子 CPP32beta，而不是ICE会阻断T细胞的凋亡。类似的研究还有 现在正在对感染艾滋病毒的T细胞进行研究，以确定这些 蛋白水解酶参与了HIV的细胞溶解作用。这些 研究将促进我们对分子机制的理解 本体型杀伤性调控途径。

This project is based on our discovery that stimulation of the antigen receptor of mature T cells following exposure of the cells to mitogenic lymphokines such as IL-2 leads to the induction of programmed cell death or apoptosis (propriocidal regulation). We are interested in the mechanism of propriocidal regulation. We are also studying whether this mechanism can explain certain phenomenon of immunological "suppression" that have been previously studied and how this mechanism plays a role in various immunomodulatory strategies being attempted for human disease. We have begun to explore the manner in which specific ways in which antigen engages the receptor affect whether or not apoptosis is induced. Using a panel of peptide variants in which different amino acids are substituted at position 99 in the 88 to 104 peptide of pigeon cytochrome c, we have found variants that will induce no IL-2 or other cytokines but still initiate T cell apoptosis. Further investigation of two such "altered peptide ligands" has shown that these do not induce the same tyrosine phosphorylation patterns of the CD3 chain, the TCRzeta chains, and the ZAP70 kinase as the 88-104 peptide. Instead, the death-inducing altered peptide ligands cause only one form of TCRzeta phosphorylation and a novel type of phosphorylation of the fyn kinase molecule. These results indicate that qualitatively different types of T cell receptor engagement may induce apoptosis through distinct signalling pathways. These findings also hold promise that certain altered peptide ligands may be potent tolerogens without a risk of causing T cell activation, which may lead to improved apoptosis-inducing therapies for T cell-mediated diseases. We have also carefully studied the types of cysteine proteases that are induced during propriocidal death. We have found that CPP32beta and ICELAP3 but not interleukin-1beta converting enzyme (ICE) are proteolytically activated during T cell death. This differs from other cell-types in which ICE appears to be activated first and play a role in the activation of CPP32beta. We also found that specific inhibitors of CPP32beta, but not ICE will block T cell apoptosis. Similar studies are now being carried out in HIV-infected T cells to determine whether these proteases take part in the cytolytic effects of HIV. These investigations will advance our understanding of the molecular mechanism of the propriocidal regulatory pathway.