Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
Lancet. 2015 Feb 26;385 Suppl 1:S25. doi: 10.1016/S0140-6736(15)60340-3.
CD4 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.
We 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.
We 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.
Our 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.
Wellcome Trust.
具有辅助性 T 细胞 1 型（Th1）和 17 型（Th17）细胞特征的 CD4 T 细胞已被牵连到几种自身免疫性疾病中，这表明 CD4 T 细胞谱系之间的可塑性可能具有致病性。然而，调节 T 细胞谱系稳定性的因素在很大程度上仍是未知的。视黄酸（RA）在炎症部位合成。我们假设，视黄酸，一种深刻的表观遗传修饰物，可以调节 T 细胞谱系稳定性。
我们使用了一种小鼠模型，通过过表达显性负性视黄酸受体 α（dnRARα 小鼠）在 T 细胞区室中特异性地消除视黄酸信号，来研究其在调节 Th1 谱系稳定性中的作用。进行了全基因组 ChIP-seq 分析以鉴定 RARα 靶标。同时，我们进行了调节区域（称为增强子）的全局作图，以深入了解视黄酸对 T 细胞命运的调节机制。通过口服抗原诱导的肠道炎症模型确定了我们发现的体内相关性。
我们发现视黄酸对于维持 Th1 谱系至关重要。Th1 细胞中视黄酸信号的消除导致 T-bet 表达和 STAT4 活性丧失。dnRARα 小鼠的 Th1 细胞表现出增强的可塑性，出现了混合的 Th1-Th17 和 Th17 效应细胞。RARα 结合的全局分析和增强子作图表明，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。视黄酸抑制 Th1 可塑性对于维持体内适当的 Th 细胞反应和防止自身免疫性肠道炎症至关重要。
我们的研究已经确定 RA-RARα 是调节 Th1 细胞维持和可塑性的调控网络的关键组成部分，并定义了一种新的途径来开发致病性 Th17 细胞。类视黄醇可能是治疗 Th17 相关自身免疫性疾病的新型治疗药物。
惠康信托基金会。
