Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
J Immunol. 2011 Mar 15;186(6):3373-82. doi: 10.4049/jimmunol.1003216. Epub 2011 Feb 9.
Plasticity within Th cell populations may play a role in enabling site-specific immune responses to infections while limiting tissue destruction. Epigenetic processes are fundamental to such plasticity; however, to date, most investigations have focused on in vitro-generated T cells. In this study, we have examined the molecular mechanisms underpinning murine Th17 plasticity in vivo by assessing H3K4 and H3K27 trimethylation marks at Tbx21, Rorc, Il17a, Ifng, and Il12rb2 loci in purified ex vivo-isolated and in vitro-generated Th17 cells. Although both populations had largely comparable epigenetic signatures, including bivalent marks at Tbx21, freshly isolated ex vivo Th17 cells displayed restricted expression from Il12rb2 due to the presence of repressive chromatin modifications. This receptor, however, could be upregulated on isolated ex vivo Th17 cells after in vitro activation or by in vivo immunization and was augmented by the presence of IFN-γ. Such activated cells could then be deviated toward a Th1-like profile. We show that IL-12 stimulation removes H3K27 trimethylation modifications at Tbx21/T-bet leading to enhanced T-bet expression with in vitro Th17 cells. Our study reveals important potential phenotypic differences between ex vivo- and in vitro-generated Th17 cells and provides mechanistic insight into Th17 cell plasticity.
Th 细胞群体的可塑性可能在使感染的特定部位免疫反应成为可能，同时限制组织破坏方面发挥作用。表观遗传过程对于这种可塑性至关重要；然而，迄今为止，大多数研究都集中在体外生成的 T 细胞上。在这项研究中，我们通过评估 Tbx21、Rorc、Il17a、Ifng 和 Il12rb2 基因座处 H3K4 和 H3K27 三甲基化标记，研究了体内小鼠 Th17 可塑性的分子机制，这些标记在体外分离和生成的 Th17 细胞中都存在。尽管这两种细胞群都具有很大的相似的表观遗传特征，包括 Tbx21 上的二价标记，但由于存在抑制性染色质修饰，新鲜分离的体外 Th17 细胞显示出对 Il12rb2 的限制表达。然而，该受体可以在体外激活后或体内免疫接种后在分离的体外 Th17 细胞上上调，并通过 IFN-γ 的存在增强。这样的激活细胞可以向 Th1 样表型分化。我们表明，IL-12 刺激会去除 Tbx21/T-bet 处的 H3K27 三甲基化修饰，导致体外 Th17 细胞中 T-bet 表达增强。我们的研究揭示了体外和体外生成的 Th17 细胞之间的重要潜在表型差异，并提供了 Th17 细胞可塑性的机制见解。
