MOLECULAR PATHWAYS INVOLVED IN THE PROGRAMMED DEATH OF LYMPHOCYTES

这个项目研究了控制细胞生长的分子途径。 成熟外周免疫中T细胞的程序性死亡 系统。解决了五个方面的问题：1)协同刺激的作用 和共受体相互作用在调节T细胞受体诱导的 死亡信号，2)成熟T淋巴细胞中Fas和肿瘤坏死因子的参与 死亡，3)P53、Bcl2、BclX等的相对重要性 成熟T淋巴细胞的凋亡调节因子，4)鉴定 Fas和肿瘤坏死因子的下游介体诱导的细胞凋亡 T细胞淋巴因子撤除细胞凋亡的分子途径 细胞。我们比较了激活的信号需求和 T细胞受体(TCR)驱动的程序性细胞死亡(PCD)所需的。 我们发现，连接CD4共受体而不是CD28 共刺激分子强烈影响TCR诱导的PCD。我们有 发现成熟的CD4T细胞的凋亡可能是相互作用的结果 Fas(Apo-1/CD95)与Fas配体之间的关系 细胞是由肿瘤坏死因子(TNF)引起的。对小白鼠的分析 P55或p75肿瘤坏死因子受体基因纯合子零突变表明 P75受体足以诱导T细胞凋亡。我们发现， TCR诱导Fas配体和Fas的主动死亡途径 肿瘤坏死因子不受P53、Bcl2或BclX的影响 在其他情况下调节淋巴细胞的凋亡。我们已经证明了 Fas或肿瘤坏死因子受体的结合导致一种 一组特殊的半胱氨酸蛋白酶，称为半胱氨酸酶，它执行 导致细胞程序性死亡的特定蛋白分解事件。我们有 发现了这些酶的一种新的细胞底物，这种底物被切割 在Fas诱导的未转化T淋巴细胞死亡过程中。最近一次 我们已经发现酪氨酸磷酸化事件与 T细胞淋巴因子撤除后的细胞凋亡。我们正在调查 这些信号事件的功能重要性和分子触发机制 要了解这种被动淋巴细胞死亡的形式，可能会发挥一种 在T细胞内稳态中起重要作用。这些研究将结合在一起 提供对控制T细胞的分子途径的重要见解 细胞凋亡在调节T细胞依赖性中的重要作用 免疫反应。

This project investigates the molecular pathways that govern the programmed death of T lineage cells in the mature peripheral immune system. Five areas have been addressed: 1) The role of co-stimulatory and co-receptor interactions in modulating a T cell receptor-induced death signal, 2) The involvement of Fas and TNF in mature T lymphocyte death, 3) The relative importance of p53, Bcl-2, Bcl-X and other regulators of apoptosis in mature T lymphocytes, 4) Identification of downstream mediators of Fas and TNF-induced apoptosis, and 5) The molecular pathway that leads to lymphokine withdrawal apoptosis in T cells. We compared the signaling requirements for activation to those required for T cell receptor (TCR)-driven programmed cell death (PCD). We found that ligation of the CD4 co-receptor but not the CD28 co-stimulatory molecule strongly influenced TCR-induced PCD. We have found that apoptosis in mature CD4 T cells can result from interactions between Fas (Apo-1/CD95) and Fas ligand whereas that of mature CD8 T cells is due to tumor necrosis factor (TNF). Analyses of mice with homozygous null mutations in the p55 or p75 TNF receptor genes show that the p75 receptor is sufficient for T cell apoptosis. We have found that the active death pathway resulting from TCR induction of Fas ligand and TNF is not influenced by p53, Bcl-2, or Bcl-X which have a role in regulating lymphocyte apoptosis in other contexts. We have shown that engagement of Fas or the TNF receptor results in the activation of a special set of cysteine proteases, termed caspases, that carry out specific proteolytic events leading to programmed cell death. We have identified a novel cellular substrate for these enzymes that is cleaved during Fas-induced death of non-transformed T lymphocytes. Most recently we have found tyrosine phosphorylation events that are associated with lymphokine withdrawal apoptosis in T cells. We are investigating the functional importance and molecular triggers of these signalling events to understand this form of passive lymphocyte death that may play an important role in T cell homeostasis. Together these studies will provide important insights into the molecular pathways that control T cell apoptosis which plays a vital role in regulating T cell-dependent immune responses.