Gonzalez-Garcia A, R-Borlado L, Leonardo E, Merida I, Martinez-A C, Carrera A C
Department of Immunology and Oncology, National Center of Biotechnology, Superior Council of Scientific Investigations, University Autonoma, Madrid, Spain.
J Immunol. 1997 May 1;158(9):4104-12.
Apoptotic cell death is induced in mature cycling T cells upon ligation of the Ag-specific TCR. This process is essential for the maintenance of homeostasis in the immune system, as it is capable of down-regulating ongoing immune responses. The analysis of the mechanism underlying TCR-induced programmed cell death has focused the attention of many scientists recently. In this regard, several recent reports have implicated Fas/Fas-ligand molecules as the final mediators of this process. Several other gene products have been implicated in the control of apoptosis (as Bcl-2, p53, and c-Myc); however, no information was available in the early signaling molecules that trigger this phenomena. The results presented in this work indicate that pp56(lck) src family kinase is actually required for the TCR to trigger cell death in mature cycling T cells. In fact, while inhibition of pp56(lck) expression with antisense oligonucleotides blocked TCR-induced apoptosis, pharmacologic inhibition of phosphatidylinositol 3-kinase activity had no effect. Accordingly, ligation of the Ag receptor in a cell line defective for pp56(lck) expression was unable to induce apoptosis, although it induced cellular stimulation, as measured by the expression of CD69. In addition, we show in this work that expression of constitutively active pp56(lck) mutants, but not pp59(fyn) mutants, in the absence of any other TCR-derived signal, is sufficient to induce apoptosis not only in transformed, but also in normal cycling T cells. Finally, evidence is presented indicating that a mechanism through which pp56(lck) regulates TCR-induced apoptosis in mature cycling T cells is by controlling Fas-ligand expression.
当抗原特异性TCR发生连接时，成熟的循环T细胞会诱导凋亡性细胞死亡。这一过程对于维持免疫系统的稳态至关重要，因为它能够下调正在进行的免疫反应。TCR诱导程序性细胞死亡的潜在机制分析最近吸引了许多科学家的关注。在这方面，最近的几份报告表明Fas/Fas配体分子是这一过程的最终介质。其他几种基因产物也与细胞凋亡的控制有关（如Bcl-2、p53和c-Myc）；然而，对于触发这一现象的早期信号分子却一无所知。这项工作中呈现的结果表明，pp56(lck) src家族激酶实际上是TCR在成熟循环T细胞中触发细胞死亡所必需的。事实上，用反义寡核苷酸抑制pp56(lck)的表达可阻断TCR诱导的细胞凋亡，而对磷脂酰肌醇3激酶活性的药理学抑制则没有效果。因此，在一个pp56(lck)表达缺陷的细胞系中，抗原受体的连接虽然能诱导细胞刺激（通过CD69的表达来衡量），但却无法诱导细胞凋亡。此外，我们在这项工作中还表明，在没有任何其他TCR衍生信号的情况下，组成型活性pp56(lck)突变体（而非pp59(fyn)突变体）的表达不仅足以在转化细胞中，而且在正常循环T细胞中诱导细胞凋亡。最后，有证据表明，pp56(lck)调节成熟循环T细胞中TCR诱导的细胞凋亡的机制是通过控制Fas配体的表达。
