Role of retinoic acid in the stability of the T-helper-type 1 lineage and implications for autoimmunity.
Role of retinoic acid in the stability of the T-helper-type 1 lineage and implications for autoimmunity.
复制标题
视黄酸在 T 辅助细胞 1 型谱系稳定性中的作用及其对自身免疫的影响。
DOI：
10.1016/s0140-6736(15)60340-3
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Brown C
中科院分区：
文献类型：
--
作者：
Brown C
背景具有辅助性T细胞1型(Th1)和17型(Th17)细胞特征的CD4 T细胞与多种自身免疫性疾病有关，表明CD4 T细胞谱系之间的可塑性具有潜在的致病性。然而，调节 T 细胞谱系稳定性的因素在很大程度上尚不清楚。视黄酸 (RA) 在炎症部位合成。我们假设视黄酸是一种重要的表观遗传修饰剂，可以调节 T 细胞谱系稳定性。方法我们使用小鼠模型来研究其在调节 Th1 谱系稳定性中的作用，其中视黄酸信号传导通过显性失活视黄酸受体 α (RARα) 的过表达在 T 细胞区室中被特异性消除（dnRARα 小鼠）。进行全基因组 ChIP-seq 分析以确定 RARα 靶标。与此同时，我们对调节区域（称为增强子）进行了全局绘图，以深入了解视黄酸对 T 细胞命运的调节。我们的研究结果的体内相关性是在口服抗原诱导的肠道炎症模型中确定的。研究结果我们发现视黄酸对于维持 Th1 谱系至关重要。 Th1 细胞中视黄酸信号传导的消除导致 T-bet 表达和 STAT4 活性丧失。随着混合 Th1-Th17 和 Th17 效应细胞的出现，来自 dnRARα 小鼠的 Th1 细胞表现出增强的可塑性。 RARα 结合和增强子作图的全局分析表明，RA–RARα 直接调节 Th1 谱系定义基因的增强子活性，同时抑制调节 Th17 细胞命运的基因。视黄酸对 Th1 可塑性的抑制对于维持体内适当的 Th 细胞反应和预防自身免疫性肠道炎症至关重要。我们的研究已确定 RA–RARα 是控制 Th1 细胞维持和可塑性的调控网络的关键组成部分，并定义了致病性 Th17 细胞发育的新途径。类视黄醇可能是治疗 Th17 相关自身免疫性疾病的新型治疗剂。FundingWellcome Trust。
BackgroundCD4 T cells with features of both T-helper-type 1 (Th1) and 17 (Th17) cells have been implicated in several autoimmune diseases suggesting that plasticity among CD4 T-cell lineages is potentially pathogenic. However, the factors that regulate T-cell lineage stability are largely unknown. Retinoic acid (RA) is synthesised at sites of inflammation. We hypothesised that retinoic acid, a profound epigenetic modifier, could regulate T-cell lineage stability.MethodsWe used a mouse model in which retinoic acid signalling is specifically ablated within the T-cell compartment through overexpression of a dominant negative retinoic acid receptor α (RARα) (dnRARα mice) to investigate its role in the regulation of Th1 lineage stability. Genome-wide ChIP-seq analysis was done to identify RARα targets. In parallel, we performed global mapping of regulatory regions, termed enhancers, to gain mechanistic insight into retinoic acid regulation of T-cell fate. The in-vivo relevance of our findings was determined in a model of oral antigen-induced intestinal inflammation.FindingsWe found that retinoic acid is crucial for maintenance of the Th1 lineage. Abrogation of retinoic acid signalling in Th1 cells resulted in loss of T-bet expression and STAT4 activity. Th1 cells from dnRARα mice showed enhanced plasticity with the emergence of hybrid Th1–Th17 and Th17 effector cells. Global analysis of RARα binding and enhancer mapping revealed that RA–RARα directly regulated enhancer activity at Th1 lineage defining genes while repressing genes that regulate Th17 cell fate. Retinoic acid inhibition of Th1 plasticity was essential for maintaining appropriate Th cell responses in vivo and preventing autoimmune intestinal inflammation.InterpretationOur study has identified RA–RARα as a key component of the regulatory network governing maintenance and plasticity of Th1 cells and defines a new pathway for the development of pathogenic Th17 cells. Retinoids might be novel therapeutic agents for Th17-associated autoimmune diseases.FundingWellcome Trust.