Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada;
J Immunol. 2014 Feb 15;192(4):1681-92. doi: 10.4049/jimmunol.1203272. Epub 2014 Jan 24.
HIV-1 infection causes depletion and/or dysfunction of distinct CD4(+) T cell subsets and may affect these differently. Using the CD4C/HIV-1(Nef) transgenic (Tg) mice as a model, we report that HIV-1 Nef causes depletion of total CD4(+) T cells, but preserves and relatively enriches CD4(+) regulatory T cells (Treg). We found that Nef-mediated CD4(+) Treg enrichment is the direct result of Nef expression in CD4(+) T cells, occurs independently of Nef-induced lymphopenia, and most likely results from multiple mechanisms: lower apoptosis, enhanced cell division, and increased generation from precursors. Interestingly, Tg Treg relative enrichment could be reversed by enhancing Lck activity. Most importantly, we show that, in contrast to Tg helper CD4(+) T cells that have lost their function, Nef-expressing CD4(+) Treg retain their regulatory function in vitro and also in vivo, under some settings. In particular, we found that Treg prevent expansion of Tg B and non-Treg T cells in vivo. Our study reveals that Nef affects distinct CD4(+) T cell subsets differently and uncovers the high proliferative potential of B and non-Treg T cells in this mouse model.
HIV-1 感染会导致不同的 CD4(+)T 细胞亚群耗竭和/或功能障碍，并且可能以不同的方式影响这些亚群。我们使用 CD4C/HIV-1(Nef)转基因 (Tg) 小鼠作为模型，报告称 HIV-1 Nef 导致总 CD4(+)T 细胞耗竭，但保留并相对富集 CD4(+)调节性 T 细胞 (Treg)。我们发现，Nef 介导的 CD4(+)Treg 富集是 Nef 在 CD4(+)T 细胞中表达的直接结果，独立于 Nef 诱导的淋巴细胞减少，并且很可能是多种机制的结果：较低的细胞凋亡、增强的细胞分裂和从前体细胞增加的产生。有趣的是，通过增强 Lck 活性可以逆转 Tg Treg 的相对富集。最重要的是，我们表明，与失去功能的 Tg 辅助性 CD4(+)T 细胞相反，表达 Nef 的 CD4(+)Treg 在体外和某些情况下在体内保留其调节功能。特别是，我们发现 Treg 可防止 Tg B 细胞和非 Treg T 细胞在体内的扩增。我们的研究揭示了 Nef 对不同的 CD4(+)T 细胞亚群的影响不同，并揭示了这种小鼠模型中 B 细胞和非 Treg T 细胞的高增殖潜力。
