Berndt C, Möpps B, Angermüller S, Gierschik P, Krammer P H
Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12556-61. doi: 10.1073/pnas.95.21.12556.
AIDS is characterized by a progressive decrease of CD4(+) helper T lymphocytes. Destruction of these cells may involve programmed cell death, apoptosis. It has previously been reported that apoptosis can be induced even in noninfected cells by HIV-1 gp120 and anti-gp120 antibodies. HIV-1 gp120 binds to T cells via CD4 and the chemokine coreceptor CXCR4 (fusin/LESTR). Therefore, we investigated whether CD4 and CXCR4 mediate gp120-induced apoptosis. We used human peripheral blood lymphocytes, malignant T cells, and CD4/CXCR4 transfectants, and found cell death induced by both cell surface receptors, CD4 and CXCR4. The induced cell death was rapid, independent of known caspases, and lacking oligonucleosomal DNA fragmentation. In addition, the death signals were not propagated via p56(lck) and Gialpha. However, the cells showed chromatin condensation, morphological shrinkage, membrane inversion, and reduced mitochondrial transmembrane potential indicative of apoptosis. Significantly, apoptosis was exclusively observed in CD4(+) but not in CD8(+) T cells, and apoptosis triggered via CXCR4 was inhibited by stromal cell-derived factor-1, the natural CXCR4 ligand. Thus, this mechanism of apoptosis might contribute to T cell depletion in AIDS and might have major implications for therapeutic intervention.
艾滋病的特征是CD4(+)辅助性T淋巴细胞进行性减少。这些细胞的破坏可能涉及程序性细胞死亡，即细胞凋亡。此前有报道称，HIV-1 gp120和抗gp120抗体甚至可在未感染的细胞中诱导细胞凋亡。HIV-1 gp120通过CD4和趋化因子共受体CXCR4（融合素/LESTR）与T细胞结合。因此，我们研究了CD4和CXCR4是否介导gp120诱导的细胞凋亡。我们使用了人外周血淋巴细胞、恶性T细胞和CD4/CXCR4转染细胞，发现细胞表面受体CD4和CXCR4均可诱导细胞死亡。诱导的细胞死亡迅速，不依赖于已知的半胱天冬酶，且缺乏寡核小体DNA片段化。此外，死亡信号不是通过p56(lck)和Gialpha传播的。然而，细胞表现出染色质浓缩、形态缩小、膜反转以及线粒体跨膜电位降低，这些都是细胞凋亡的指征。值得注意的是，细胞凋亡仅在CD4(+) T细胞中观察到，而在CD8(+) T细胞中未观察到，并且通过CXCR4触发的细胞凋亡受到基质细胞衍生因子-1（天然CXCR4配体）的抑制。因此，这种细胞凋亡机制可能导致艾滋病中的T细胞耗竭，并且可能对治疗干预具有重要意义。
