Holmes Derek, Knudsen Geoffry, Mackey-Cushman Stephanie, Su Lishan
Department of Microbiology and Immunology, the Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill 27599-7295, USA.
J Biol Chem. 2007 Jun 1;282(22):15973-80. doi: 10.1074/jbc.M702051200. Epub 2007 Apr 6.
FoxP3 determines the development of CD4+CD25+ regulatory T (Treg) cells and represses interleukin-2 (IL-2) expression in Treg cells. However, human immunodeficiency virus type 1 (HIV-1) infects and replicates efficiently in FoxP3+ Treg cells. We report that, while inhibiting IL-2 gene expression, FoxP3 enhances gene expression from HIV-1 long terminal repeat (LTR). This FoxP3 activity requires both the N- and C-terminal domains and is inactivated by human IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) mutations. FoxP3 enhances HIV-1 LTR via its specific NFkappaB binding sequences in an NFkappaB-dependent fashion in T cells but not in HEK293 cells. FoxP3 decreases level of histone acetylation at the interleukin-2 locus but not at the HIV-1 LTR. Although NFkappaB nuclear translocation is not altered, FoxP3 enhances NFkappaB-p65 binding to HIV-1 LTR. These data suggest that FoxP3 modulates gene expression in a promoter sequence-dependent fashion by modulating chromatin structure and NFkappaB activity. HIV-1 LTR has evolved to both highjack the T-cell activation pathway for expression and to resist FoxP3-mediated suppression of T-cell activation.
FoxP3决定CD4+CD25+调节性T（Treg）细胞的发育，并抑制Treg细胞中白细胞介素-2（IL-2）的表达。然而，1型人类免疫缺陷病毒（HIV-1）能在FoxP3+ Treg细胞中高效感染和复制。我们报告称，在抑制IL-2基因表达的同时，FoxP3增强了HIV-1长末端重复序列（LTR）的基因表达。这种FoxP3活性需要N端和C端结构域，并且会被人类IPEX（免疫失调、多内分泌腺病、肠病、X连锁综合征）突变所灭活。在T细胞而非HEK293细胞中，FoxP3通过其特定的NFκB结合序列以NFκB依赖的方式增强HIV-1 LTR。FoxP3降低了白细胞介素-2基因座处的组蛋白乙酰化水平，但对HIV-1 LTR处的组蛋白乙酰化水平没有影响。尽管NFκB的核转位没有改变，但FoxP3增强了NFκB-p65与HIV-1 LTR的结合。这些数据表明，FoxP3通过调节染色质结构和NFκB活性，以启动子序列依赖的方式调节基因表达。HIV-1 LTR已经进化到既能劫持T细胞激活途径以进行表达，又能抵抗FoxP3介导的T细胞激活抑制。
