Department of Microbiology and Immunology, Keio University School of, Medicine, Tokyo, Japan.
Int Immunol. 2011 Jul;23(7):433-41. doi: 10.1093/intimm/dxr031. Epub 2011 Jun 3.
The viral protein Nef is a key element for the progression of HIV disease. Previous in vitro studies suggested that Nef expression in T-cell lines enhanced TCR signaling pathways upon stimulation with TCR cross-linking, leading to the proposal that Nef lowers the threshold of T-cell activation, thus increasing susceptibility to viral replication in immune response. Likewise, the in vivo effects of Nef transgenic mouse models supported T-cell hyperresponse by Nef. However, the interpretation is complicated by Nef expression early in the development of T cells in these animal models. Here, we analyzed the consequence of Nef expression in ovalbumin-specific/CD4(+) peripheral T cells by using a novel mouse model and demonstrate that Nef inhibits antigen-specific T-cell proliferation and multiple functions required for immune response in vivo, which includes T-cell helper activity for the primary and memory B-cell response. However, Nef does not completely abrogate T-cell activity, as defined by low levels of cytokine production, which may afford the virus a replicative advantage. These results support a model, in which Nef expression does not cause T-cell hyperresponse in immune reaction, but instead reduces the T-cell activity, that may contribute to a low level of virus spread without viral cytopathic effects.
病毒蛋白 Nef 是 HIV 疾病进展的关键因素。先前的体外研究表明，Nef 在 T 细胞系中的表达在 TCR 交联刺激下增强了 TCR 信号通路，从而提出 Nef 降低了 T 细胞激活的阈值，从而增加了对免疫反应中病毒复制的易感性。同样，Nef 转基因小鼠模型的体内效应也支持 Nef 引起 T 细胞的高反应性。然而，由于这些动物模型中 Nef 在 T 细胞发育早期表达，因此解释变得复杂。在这里，我们通过使用新型小鼠模型分析了 Nef 在卵清蛋白特异性/CD4(+)外周 T 细胞中的表达的后果，并证明 Nef 抑制体内抗原特异性 T 细胞增殖和免疫反应所需的多种功能，包括对原发性和记忆 B 细胞反应的 T 细胞辅助活性。然而，Nef 并没有完全消除 T 细胞的活性，因为细胞因子产生水平较低，这可能使病毒具有复制优势。这些结果支持这样一种模型，即 Nef 的表达不会在免疫反应中引起 T 细胞的高反应性，而是降低 T 细胞的活性，这可能有助于病毒在没有病毒细胞病变作用的情况下低水平传播。
