Retinoic acid signaling constrains the plasticity of Th1 cells and prevents development of pathogenic Th17 cells [Affymetrix experiments]. Mus musculus

CD4+ T cells differentiate into phenotypically distinct T-helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune diseases. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARa, sustains stable expression of Th1 lineage specifying genes as well as repressing genes that instruct Th17 cell fate. RA signaling is essential for limiting Th1 cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our studies identify RA-RARa as a key component of the regulatory network governing Th1 cell fate and define a new paradigm for the development of pathogenic Th17 cells. These findings have important implications for autoimmune diseases in which dysregulated Th1-Th17 responses are observed. Overall design: IFN-gamma+ Th1 cells from IFNgeYFP reporter mouse; comparing dnRARa to WT

抗原刺激后，CD4+ T细胞可分化为表型各异的辅助性T细胞（T-helper cells, Th）。调控此类CD4+ T细胞谱系间的可塑性，对于维持免疫稳态（immune homeostasis）以及预防自身免疫病至关重要。然而，调控该谱系稳定性的核心因子在很大程度上仍未被阐明。本研究以传统上被认为是表型最稳定的Th亚群——1型辅助性T细胞（T helper 1, Th1）为模型，探究视黄酸（retinoic acid, RA）在调控谱系稳定性中的作用。我们发现，视黄酸（RA）可通过其受体视黄酸受体α（retinoic acid receptor α, RARα），维持Th1谱系特异性基因的稳定表达，同时抑制指导17型辅助性T细胞（T helper 17, Th17）命运的基因转录。视黄酸信号通路对于限制Th1细胞向Th17效应细胞转化，以及在体内阻断致病性Th17应答均不可或缺。本研究证实RA-RARα信号轴是调控Th1细胞命运的核心调控网络组分，并为致病性Th17细胞的发育确立了全新的研究范式。上述发现对于存在Th1-Th17应答失调的自身免疫病研究具有重要的潜在指导意义。实验整体设计：取自IFNγ-eYFP报告基因小鼠的IFN-γ+ Th1细胞；对比显性负效RARα（dnRARα）与野生型（WT）样本。