PROGRAMMED CELL DEATH IN LYMPHOCYTES

我们继续研究程序化细胞的机制， 死亡（PCD）途径触发的T细胞受体（TcR）， 功能成熟的T细胞，并定义了三种不同的死亡 途径。 第一种是在T细胞杂交瘤中发现的，激活的外周T细胞 细胞和来自HIV+供体的血液T细胞，并涉及Fas和Fas 配体 激活通过钙蛋白酶依赖性上调Fas配体 途径，引起Fas触发的细胞死亡。 该途径 当杂交瘤被钙蛋白酶特异性 抑制剂钙蛋白酶抑制剂，以及其他蛋白酶抑制剂。 它 在由TcR触发的正常CD 4+和CD 8 + T细胞母细胞中起作用， 但不参与这些细胞中的其它凋亡性死亡途径。 基于蛋白酶抑制剂阻断细胞死亡， 当来自HIV+供体的T细胞被超抗原激活时。 在这 通过蛋白酶抑制剂阻断这种TcR诱导的死亡途径 可以激活反应，逆转辅助性T细胞功能， 之前描述的缺陷。 第二次TcR诱导的死亡反应 发生更缓慢，并由TNF或α-光毒素介导。 我们有 发现激活的T细胞可以在体外死亡， 细胞因子，先前发现其仅杀死肿瘤细胞。 这种死亡过程是由一种混合抗体触发的， 两种TNF受体，并被RNA和蛋白质合成阻断 抑制剂以及细胞因子IL-2和IL-12。 第三个TcR- 当严格纯化的静息T细胞 将来自血液、淋巴结或脾的细胞暴露于抗CD 3过夜， 体外 这种死亡以前没有见过，因为它是封闭的， 通过多种巨噬细胞和T细胞衍生的细胞因子， 正常存在。 这种默认的死亡途径发生在Fas配体 突变株gld，并且不被抗Fas抗体阻断，表明 一种新的尚未确定的死亡分子途径 这些结果 认为生存信号是正常T细胞激活所必需的; 除了TcR之外，还需要第三种细胞内信号， 共刺激，虽然它通常是通过IL-2产生的， 这是前两个信号的结果。

We have continued investigating the mechanisms of programmed cell death (PCD) pathway triggered by the T cell receptor (TcR) in functionally mature T cells, and have defined three distinct death pathways. The first is found in T hybridomas, activated peripheral T cells, and blood T cells from HIV+ donors, and involves Fas and Fas Ligand. Activation upregulates Fas Ligand via a calpain-dependent pathway, giving rise to cell death triggered by Fas. This pathway is blocked when hybridomas are transfected by the calpain-specific inhibitor calpastatin, as well as by other protease inhibitors. It operates in normal CD4+ and CD8+ T cell blasts triggered by the TcR, but is not involved in other apoptotic death pathways in these cells. Based on blocking cell death by protease inhibitors, it also operates when T cells from HIV+ donors are activated by superantigen. In this setting blocking this TcR-induced death pathway by protease inhibitors can allow an activation response, reversing the T helper functional deficiency previously described. A second TcR-induced death response occurs more slowly and is mediated by TNF or lymphotoxin. We have found that activated T cell can die in vitro in response to these cytokines, which have previously been found to kill only tumor cells. This death process is triggered by a mixture of antibodies against both TNF receptors, and is blocked by RNA and protein synthesis inhibitors as well as the cytokines IL-2 and IL-12. A third TcR- induced death response occurs when rigorously purified resting T cells from blood, lymph node, or spleen are exposed to anti-CD3 overnight in vitro. This death has not previously been seen because it is blocked by a variety of macrophage- and T cell-derived cytokines which are normally present. This default death pathway occurs in the Fas Ligand mutant strain gld, and is not blocked by anti-Fas antibody, suggesting a new as-yet- undefined molecular pathway of death. These results argue that a survival signal is required for normal T cell activation; this third intracellular signal is required in addition to the TcR and costimulation, although it normally occurs via IL-2 produced as a consequence of the first two signals.