Ledru E, Lecoeur H, Garcia S, Debord T, Gougeon M L
Département SIDA et Rétrovirus, Institut Pasteur, Paris, France.
J Immunol. 1998 Apr 1;160(7):3194-206.
It has been proposed that HIV infection is associated with an imbalance in Th1 and Th2 subsets. Recent reports indicate that Th1 and Th2 effectors differ in their susceptibility to activation-induced apoptosis. To determine whether increased T cell apoptosis in HIV-infected patients contributes to alterations in cytokine synthesis, we performed single-cell analysis of type 1 and type 2 cytokine production by CD4 and CD8 T cells, simultaneously with detection of apoptosis. We demonstrate that a differential alteration in representation of Th1 subsets, rather than commitment of T cells to secrete Th2 cytokines, occurs throughout HIV infection. A significant decrease in the number of IL-2- or TNF-alpha-producing T cells was observed, whereas those producing IFN-gamma remained preserved. Furthermore, there is a gradient of susceptibility to activation-induced apoptosis (IL-2 < IFN-gamma < TNF-alpha) among the different Th1 subsets. This gradient was detected in both CD4 and CD8 subsets, as well as in control donors and HIV-infected patients, in whom the susceptibility to apoptosis of IL-2 and IFN-gamma producers was increased compared with controls. This differential intrinsic apoptosis susceptibility of Th1 effectors was found to be tightly regulated by Bcl-2 expression. In HIV-infected persons, disappearance of IL-2-producing T cells was a good indicator of disease progression and was correlated with the progressive shrinkage of the CD4+ CD45RA+ T cell compartment and a gradual increased susceptibility to activation-induced apoptosis of the IL-2-producing subset. This close relationship between the CD45RA/CD45R0 ratio, the level of type 1 cytokine production, and susceptibility to apoptosis should be considered in HIV-infected patients under antiviral or immune-based therapies.
有人提出，HIV感染与Th1和Th2亚群失衡有关。最近的报告表明，Th1和Th2效应细胞在对激活诱导的凋亡的易感性方面存在差异。为了确定HIV感染患者中T细胞凋亡增加是否导致细胞因子合成改变，我们对CD4和CD8 T细胞产生的1型和2型细胞因子进行了单细胞分析，同时检测凋亡情况。我们证明，在整个HIV感染过程中，Th1亚群的代表性发生了差异性改变，而不是T细胞倾向于分泌Th2细胞因子。观察到产生IL-2或TNF-α的T细胞数量显著减少，而产生IFN-γ的T细胞数量保持不变。此外，不同Th1亚群之间对激活诱导的凋亡的易感性存在梯度（IL-2 < IFN-γ < TNF-α）。在CD4和CD8亚群中，以及在对照供体和HIV感染患者中都检测到了这种梯度，与对照相比，IL-2和IFN-γ产生细胞的凋亡易感性增加。发现Th1效应细胞这种差异性的内在凋亡易感性受到Bcl-2表达的严格调控。在HIV感染者中，产生IL-2的T细胞消失是疾病进展的一个良好指标，并且与CD4+ CD45RA+ T细胞区室的逐渐缩小以及产生IL-2的亚群对激活诱导的凋亡的易感性逐渐增加相关。在接受抗病毒或基于免疫的治疗的HIV感染患者中，应考虑CD45RA/CD45R0比值、1型细胞因子产生水平与凋亡易感性之间的这种密切关系。
