Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Viruses. 2018 May 27;10(6):287. doi: 10.3390/v10060287.
CD8⁺ T cells are critical for controlling HIV infection. During the chronic phase of lentiviral infection, CD8⁺ T cells lose their proliferative capacity and exhibit impaired antiviral function. This loss of CD8⁺ T cell function is due, in part, to CD4⁺CD25⁺ T regulatory (Treg) cell-mediated suppression. Our research group has demonstrated that lentivirus-activated CD4⁺CD25⁺ Treg cells induce the repressive transcription factor forkhead box P3 (Foxp3) in autologous CD8⁺ T cells following co-culture. We have recently reported that Treg-induced Foxp3 binds the interleukin-2 (IL-2), interferon-γ (IFN- γ), and tumor necrosis factor-α (TNF-α) promoters in virus-specific CD8⁺ T cells. These data suggest an important role of Foxp3-mediated CD8⁺ T cell dysfunction in lentiviral infection. To elucidate the mechanism of this suppression, we previously reported that decreased methylation facilitates Foxp3 binding in mitogen-activated CD8⁺ T cells from feline immunodeficiency virus (FIV)-infected cats. We demonstrated the reduced binding of Foxp3 to the IL-2 promoter by increasing methylation of CD8⁺ T cells. In the studies presented here, we ask if another form of epigenetic modulation might alleviate Foxp3-mediated suppression in CD8⁺ T cells. We hypothesized that decreasing histone acetylation in virus-specific CD8⁺ T cells would decrease Treg-induced Foxp3 binding to the IL-2 promoter. Indeed, using anacardic acid (AA), a known histone acetyl transferase (HAT) inhibitor, we demonstrate a reduction in Foxp3 binding to the IL-2 promoter in virus-specific CD8⁺ T cells co-cultured with autologous Treg cells. These data identify a novel mechanism of Foxp3-mediated CD8⁺ T cell dysfunction during lentiviral infection.
CD8⁺ T 细胞对于控制 HIV 感染至关重要。在慢病毒感染的慢性阶段，CD8⁺ T 细胞失去增殖能力，并表现出抗病毒功能受损。CD8⁺ T 细胞功能的丧失部分归因于 CD4⁺CD25⁺调节性 T 细胞（Treg）介导的抑制作用。我们的研究小组已经证明，在共培养后，慢病毒激活的 CD4⁺CD25⁺Treg 细胞会诱导自体 CD8⁺ T 细胞中抑制性转录因子叉头框 P3（Foxp3）的表达。我们最近报道称，Treg 诱导的 Foxp3 结合白细胞介素 2（IL-2）、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）启动子在病毒特异性 CD8⁺ T 细胞中。这些数据表明，Foxp3 介导的 CD8⁺ T 细胞功能障碍在慢病毒感染中起着重要作用。为了阐明这种抑制的机制，我们之前报道过，在猫免疫缺陷病毒（FIV）感染的猫的有丝分裂原激活的 CD8⁺ T 细胞中，减少甲基化有助于 Foxp3 结合。我们通过增加 CD8⁺ T 细胞的甲基化来证明 Foxp3 与 IL-2 启动子结合减少。在本研究中，我们询问另一种形式的表观遗传修饰是否可以减轻 CD8⁺ T 细胞中 Foxp3 介导的抑制作用。我们假设病毒特异性 CD8⁺ T 细胞中组蛋白乙酰化的减少会降低 Treg 诱导的 Foxp3 与 IL-2 启动子的结合。事实上，使用已知的组蛋白乙酰转移酶（HAT）抑制剂——漆树酸（AA），我们证明在与自体 Treg 细胞共培养的病毒特异性 CD8⁺ T 细胞中，Foxp3 与 IL-2 启动子的结合减少。这些数据确定了在慢病毒感染期间 Foxp3 介导的 CD8⁺ T 细胞功能障碍的一种新机制。
