Miller Michelle M, Akaronu Nnenna, Thompson Elizabeth M, Hood Sylvia F, Fogle Jonathan E
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607.
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607
J Immunol. 2015 Feb 1;194(3):990-8. doi: 10.4049/jimmunol.1401762. Epub 2014 Dec 29.
We have previously demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) activated during the course of feline immunodeficiency virus (FIV) infection suppress CD8(+) CTL function in a TGF-β-dependent fashion, inhibiting IFN-γ and IL-2 production and inducing G1 cell-cycle arrest. In this article, we describe the molecular events occurring at the IL-2 promoter leading to suppression of IL-2 production. These experiments demonstrate that Foxp3 induced by lentivirus-activated Tregs in the CD8(+) target cells binds to the IL-2 promoter, actively repressing IL-2 transcription. We further demonstrate that the chronic activation of CD8(+) T cells during FIV infection results in chromatin remodeling at the IL-2 promoter, specifically, demethylation of CpG residues. These DNA modifications occur during active transcription and translation of IL-2; however, these changes render the IL-2 promoter permissive to Foxp3-induced transcriptional repression. These data help explain, in part, the seemingly paradoxical observations that CD8(+) T cells displaying an activation phenotype exhibit altered antiviral function. Further, we demonstrate that blocking demethylation of CpG residues at the IL-2 promoter inhibits Foxp3 binding, suggesting a potential mechanism for rescue and/or reactivation of CD8(+) T cells. Using the FIV model for lentiviral persistence, these studies provide a framework for understanding how immune activation combined with Treg-mediated suppression may affect CD8(+) T cell IL-2 transcription, maturation, and antiviral function.
我们先前已证明，在猫免疫缺陷病毒（FIV）感染过程中激活的CD4(+)CD25(+)调节性T细胞（Tregs）以TGF-β依赖的方式抑制CD8(+)CTL功能，抑制IFN-γ和IL-2的产生，并诱导G1期细胞周期停滞。在本文中，我们描述了在IL-2启动子处发生的导致IL-2产生受抑制的分子事件。这些实验表明，慢病毒激活的Tregs在CD8(+)靶细胞中诱导产生的Foxp3与IL-2启动子结合，积极抑制IL-2转录。我们进一步证明，FIV感染期间CD8(+)T细胞的慢性激活导致IL-2启动子处的染色质重塑，具体而言，是CpG残基的去甲基化。这些DNA修饰发生在IL-2的活跃转录和翻译过程中；然而，这些变化使IL-2启动子易于受到Foxp3诱导的转录抑制。这些数据部分解释了看似矛盾的观察结果，即表现出激活表型的CD8(+)T细胞具有改变的抗病毒功能。此外，我们证明阻断IL-2启动子处CpG残基的去甲基化可抑制Foxp3结合，这表明了一种拯救和/或重新激活CD8(+)T细胞的潜在机制。利用FIV模型研究慢病毒的持续存在，这些研究为理解免疫激活与Treg介导的抑制如何影响CD8(+)T细胞的IL-2转录、成熟和抗病毒功能提供了一个框架。
