Walker L S, McLeod J D, Boulougouris G, Patel Y I, Ellwood C N, Hall N D, Sansom D M
Department of Pharmacology, University of Bath, Calverton Down, Bath, BA2 7AY, UK.
Immunology. 1999 Dec;98(4):569-75. doi: 10.1046/j.1365-2567.1999.00925.x.
The generation of effective immunity requires that antigen-specific T cells are activated, clonally expanded and ultimately eliminated by apoptosis. The involvement of CD95-mediated apoptosis in T-cell elimination is well established, but the conditions which regulate the death pathway under normal circumstances are still emerging. Using superantigen-activated human T cells, we found that whilst T-cell receptor (TCR) signalling triggered up-regulation of CD95 ligand (CD95L), the majority of T cells were resistant to apoptosis induction, despite co-expressing high levels of CD95. Resistance was maintained following direct antibody-mediated cross-linking of CD95 and was not confined to early time periods following activation. Our data implicate TCR-derived signals in protection from apoptosis and reveal a role for the mitogen-activated protein (MAP) kinase pathway by use of a MAP kinase kinase (MEK) inhibitor. Collectively these data demonstrate that resistance to activation-induced cell death in human T cells is prolonged rather than transient, is not attributable to a lack of CD95L up-regulation and is due, at least in part, to signalling via the MEK pathway.
有效的免疫反应产生需要抗原特异性T细胞被激活、克隆性扩增并最终通过凋亡被清除。CD95介导的凋亡在T细胞清除中的作用已得到充分证实，但在正常情况下调节死亡途径的条件仍在不断显现。使用超抗原激活的人T细胞，我们发现虽然T细胞受体（TCR）信号传导触发了CD95配体（CD95L）的上调，但大多数T细胞对凋亡诱导具有抗性，尽管它们同时高表达CD95。直接抗体介导的CD95交联后仍维持抗性，且不限于激活后的早期阶段。我们的数据表明TCR衍生信号在保护细胞免于凋亡中起作用，并通过使用丝裂原活化蛋白（MAP）激酶激酶（MEK）抑制剂揭示了丝裂原活化蛋白激酶途径的作用。这些数据共同表明，人类T细胞对激活诱导的细胞死亡的抗性是延长而非短暂的，并非由于缺乏CD95L上调，并且至少部分是由于通过MEK途径的信号传导。
