Boudet F, Lecoeur H, Gougeon M L
Retroviruses and AIDS Department, Pasteur Institute, Paris, France.
J Immunol. 1996 Mar 15;156(6):2282-93.
In this study, we have investigated whether the enhanced apoptosis of CD4+ and CD8+ T lymphocytes throughout HIV infection was controlled by the bcl-2 proto-oncogene, an inhibitor of programmed cell death (PCD) in mammals. We have analyzed the intracellular expression of the Bcl-2 protein by flow cytometry in freshly isolated peripheral T cells from HIV-infected and noninfected individuals. While no decrease in Bcl-2 expression was detected in the CD4+ T cell subset from the seropositive donors, a reduced level of Bcl-2 was found in a fraction of CD8+ T lymphocytes, with the proportion of these cells increasing as HIV infection progressed. We show that the low Bcl-2-expressing CD8+ T cells were highly susceptible to spontaneous apoptosis upon short term culture. Interestingly, PCD significantly increased when these lymphocytes were cultured in the presence of a Fas-specific mAb, which was related to the high expression of the Fas Ag on their surface. The low Bcl-2 CD8+ subpopulation displayed activation markers CD45RO, HLA-DR, and CD38 and expressed TIA-1-positive, but perforin-negative, granules, while lacking the CD28 Ag. These observations suggest that such low Bcl-2 CD8+ T cells correspond to either immature or end-staged anergic CTLs. Moreover, they indicate that down-regulation of Bcl-2 and up-regulation of Bcl-2 and up-regulation of Fas in CD8+ T lymphocytes, associated with the chronic stimulation of these cells during HIV infection, might render them sensitive to Fas-mediated PCD. Such a Bcl-2/Fas-regulated apoptosis could be responsible for the disappearance of both memory CD45RO+ T cell response and HIV-specific cytotoxic activity occurring in the course of HIV infection and could contribute to AIDS pathogenesis.
在本研究中，我们调查了在整个HIV感染过程中，CD4+和CD8+ T淋巴细胞凋亡增强是否受bcl-2原癌基因控制，该基因是哺乳动物程序性细胞死亡（PCD）的抑制剂。我们通过流式细胞术分析了从HIV感染和未感染个体新鲜分离的外周T细胞中Bcl-2蛋白的细胞内表达。虽然在血清阳性供体的CD4+ T细胞亚群中未检测到Bcl-2表达降低，但在一部分CD8+ T淋巴细胞中发现Bcl-2水平降低，并且随着HIV感染进展，这些细胞的比例增加。我们发现，低表达Bcl-2的CD8+ T细胞在短期培养后对自发凋亡高度敏感。有趣的是，当这些淋巴细胞在Fas特异性单克隆抗体存在下培养时，PCD显著增加，这与它们表面Fas抗原的高表达有关。低Bcl-2 CD8+亚群显示激活标志物CD45RO、HLA-DR和CD38，并表达TIA-1阳性但穿孔素阴性的颗粒，同时缺乏CD28抗原。这些观察结果表明，这种低Bcl-2 CD8+ T细胞对应于未成熟或终末期无反应性细胞毒性T淋巴细胞（CTL）。此外，它们表明，与HIV感染期间这些细胞的慢性刺激相关的CD8+ T淋巴细胞中Bcl-2的下调以及Fas的上调，可能使它们对Fas介导的PCD敏感。这种由Bcl-2/Fas调节的凋亡可能是HIV感染过程中记忆性CD45RO+ T细胞反应和HIV特异性细胞毒性活性消失的原因，并可能促成艾滋病发病机制。
