T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons.
T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons.
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DOI：
10.1084/jem.182.6.1759
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发表时间：
1995-12-01
期刊：
影响因子：
--
通讯作者：
Ameisen JC
中科院分区：
文献类型：
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作者：
Estaquier J;Idziorek T;Zou W;Emilie D;Farber CM;Bourez JM;Ameisen JC
人类免疫缺陷病毒 (HIV) 感染导致 CD4+ T 辅助细胞 (Th) 1 型细胞介导的免疫逐渐丧失，这与体外 CD4+ T 细胞增殖缺陷和响应 T 细胞受体 (TCR) 刺激而导致的细胞凋亡导致异常 T 细胞死亡有关。通过免疫测定法对白细胞介素 (IL)-2、干扰素 γ、IL-4、IL-5 和 IL-10 分泌进行定量，并在体外刺激 TCR 后通过竞争性逆转录酶聚合酶链反应对干扰素 γ、IL-4 和 IL-10 信使 RNA 表达进行定量，揭示了来自 HIV 感染者和来自 HIV 感染者的 T 细胞中相似的 Th1 细胞因子谱。 控制。这些数据表明，HIV感染者中CD4+ Th1细胞功能的丧失与之前提出的Th1至Th2细胞因子转换无关，而是与激活诱导的CD4+ Th1细胞死亡过程有关。尽管不存在水平升高的 Th2 细胞因子，但在体外，IL-10 或 IL-4（两种下调 Th1 细胞反应的 Th2 细胞因子）抗体或添加重组 IL-12（上调 Th1 功能的细胞因子）可以阻止 CD4+ T 细胞（而非 CD8+ T 细胞）的凋亡。 TCR 诱导的 T 细胞杂交瘤和预激活 T 细胞凋亡已被证明涉及 CD95 (Fas/Apo-1) 分子。来自 HIV 感染者的 CD4+ 和 CD8+ T 细胞表达高水平的 CD95 分子，并且与对照的 T 细胞相比，它们对抗体介导的 CD95 连接高度敏感，这会诱导一定比例的 T 细胞凋亡，与 TCR 刺激诱导的细胞凋亡相似。作为 TCR 诱导的细胞凋亡，添加重组 IL-12 可阻止 CD95 介导的 CD4+ T 细胞凋亡，但不能阻止 CD8+ T 细胞凋亡。 总之，这些发现表明，HIV 感染者的 CD4+ T 细胞凋亡涉及对 CD95 连接的异常敏感性，以及在正常水平 Th2 细胞因子存在的情况下对 TCR 刺激的异常敏感性。 IL-12 对这两种机制的预防作用对于设计旨在上调 AIDS 中 CD4+ Th1 细胞功能的免疫治疗策略具有潜在意义。
Human immunodeficiency virus (HIV) infection leads to a progressive loss of CD4+ T helper (Th) type 1 cell-mediated immunity that is associated with defective in vitro CD4+ T cell proliferation and abnormal T cell death by apoptosis in response to T cell receptor (TCR) stimulation. Quantification of interleukin (IL)-2, interferon gamma, IL- 4, IL-5, and IL-10 secretion by immunoassays, and of interferon gamma, IL-4 and IL-10 messenger RNA expression by competitive reverse transcriptase polymerase chain reaction after in vitro stimulation of the TCR revealed a similar Th1 cytokine profile in T cells from HIV- infected persons and from controls. These data indicated that the loss of CD4+ Th1 cell function in HIV-infected persons is not related to a Th1 to Th2 cytokine switch as previously proposed, but to a process of activation-induced death of CD4+ Th1 cells. Despite the absence of elevated levels of Th2 cytokines, apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented in vitro by antibodies to IL-10 or IL-4, two Th2 cytokines that downregulate Th1 cell responses, or by the addition of recombinant IL-12, a cytokine that upregulates Th1 functions. TCR-induced apoptosis of T cell hybridomas and preactivated T cells has been shown to involve the CD95 (Fas/Apo-1) molecule. CD4+ and CD8+ T cells from HIV-infected persons expressed high levels of the CD95 molecule, and, in contrast to T cells from controls, were highly sensitive to antibody-mediated CD95 ligation, which induced apoptosis in a percentage of T cells similar to that induced by TCR stimulation. As TCR-induced apoptosis, CD95-mediated apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented by the addition of recombinant IL- 12. Together, these findings suggest that apoptosis of CD4+ T cells from HIV-infected persons involves an abnormal sensitivity to CD95 ligation, and to TCR stimulation in the presence of normal levels of Th2 cytokines. The preventive effect of IL-12 on both mechanisms has potential implications for the design of immunotherapy strategies aimed at the upregulation of CD4+ Th1 cell functions in AIDS.