Cohen D A, Fitzpatrick E A, Barve S S, Guthridge J M, Jacob R J, Simmerman L, Kaplan A M
Department of Microbiology and Immunology, University of Kentucky, College of Medicine, Lexington 40536-0084.
Cell Immunol. 1993 Oct 15;151(2):392-403. doi: 10.1006/cimm.1993.1248.
The mechanism by which CD4+ T cells are depleted during HIV infection remains a matter of controversy. Recent reports have suggested that activation-induced apoptosis of antigen-specific CD4+ T cells may lead ultimately to depletion of this T cell subset during HIV infection. The murine retroviral model of AIDS (MAIDS) also displays progressive immunodeficiency, but depletion of the CD4+ T cell subset is not characteristic of the disease. We report that a fraction of splenic CD4+ T cells from 8- to 14-week MAIDS-infected C57B1/6 mice, but not normal mice, was undergoing apoptosis at the time of cell isolation. Typical apoptotic morphology and internucleosomal DNA fragmentation was seen in CD4+ T cells only from infected mice. Moreover, injection of anti-CD3 mAb enhanced DNA fragmentation in CD4+ T cells from infected but not normal mice, suggesting that the apoptosis in vivo in CD4+ T cells during MAIDS may be dependent on cell activation. Induction of apoptosis was associated with defective signaling through the TcR complex, since anti-CD3 stimulation in vitro of CD4+ T cells from infected mice caused a diminished calcium response, yet no cellular proliferation. Despite the occurrence of apoptosis in vivo in CD4+ T cells from MAIDS-infected mice, CD4+ T cells were not depleted during the course of disease. Thus, while apoptosis in CD4+ T cells is a characteristic of MAIDS immunodeficiency disease as well as HIV infections in humans, CD4+ T cell depletion is only observed in HIV infections. In view of the extensive lymphocyte expansion which occurs in vivo in MAIDS, the balance between activation-induced apoptosis and chronic cell proliferation may determine whether cell depletion is a characteristic feature of retrovirus-induced immunodeficiencies.
在HIV感染期间CD4+ T细胞耗竭的机制仍存在争议。最近的报告表明，抗原特异性CD4+ T细胞的激活诱导凋亡可能最终导致HIV感染期间该T细胞亚群的耗竭。艾滋病的鼠逆转录病毒模型（MAIDS）也表现出进行性免疫缺陷，但CD4+ T细胞亚群的耗竭不是该疾病的特征。我们报告，在细胞分离时，来自8至14周龄感染MAIDS的C57B1/6小鼠而非正常小鼠的一部分脾CD4+ T细胞正在发生凋亡。仅在感染小鼠的CD4+ T细胞中观察到典型的凋亡形态和核小体间DNA片段化。此外，注射抗CD3单克隆抗体增强了感染小鼠而非正常小鼠的CD4+ T细胞中的DNA片段化，这表明MAIDS期间CD4+ T细胞在体内的凋亡可能依赖于细胞激活。凋亡的诱导与通过TcR复合物的信号缺陷有关，因为体外抗CD3刺激感染小鼠的CD4+ T细胞导致钙反应减弱，但没有细胞增殖。尽管在感染MAIDS的小鼠的CD4+ T细胞中体内发生了凋亡，但在疾病过程中CD4+ T细胞并未耗竭。因此，虽然CD4+ T细胞凋亡是MAIDS免疫缺陷疾病以及人类HIV感染的特征，但仅在HIV感染中观察到CD4+ T细胞耗竭。鉴于MAIDS体内发生广泛的淋巴细胞扩增，激活诱导凋亡与慢性细胞增殖之间的平衡可能决定细胞耗竭是否是逆转录病毒诱导的免疫缺陷的特征性特征。
