Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
Mucosal Immunol. 2021 Jan;14(1):100-112. doi: 10.1038/s41385-020-0311-9. Epub 2020 Jun 9.
Vitamin A metabolites play important roles in T cell activation and differentiation. A conventional model of RARα function relies upon retinoic acid (RA)-liganded RARα binding to specific DNA motifs to regulate gene expression in the nucleus. However, this genomic function fails to explain many of the biological responses of the RA-RARα axis on T cells. We generated a mouse line where RARα is over-expressed in T cells to probe RARα function with unprecedented sensitivity. Using this model together with mice specifically lacking RARα in T cells, we found that RARα is required for prompt exit from metabolic quiescence in resting T cells upon T cell activation. The positive effect of RARα on metabolism is mediated through PI3K and subsequent activation of the Akt and mTOR signaling pathway. This largely non-genomic function of RARα is surprisingly ligand-independent and controls the differentiation of effector and regulatory T cell subsets.
维生素 A 代谢物在 T 细胞激活和分化中发挥重要作用。RARα 功能的传统模型依赖于视黄酸（RA）配体结合的 RARα 与特定的 DNA 基序结合，以调节细胞核中的基因表达。然而，这种基因组功能并不能解释 RA-RARα 轴对 T 细胞的许多生物学反应。我们生成了一种在 T 细胞中过表达 RARα 的小鼠品系，以空前的灵敏度探究 RARα 的功能。利用该模型以及特异性缺乏 T 细胞中 RARα 的小鼠，我们发现 RARα 是 T 细胞激活后静止 T 细胞快速退出代谢静止所必需的。RARα 对代谢的正向影响是通过 PI3K 介导的，随后激活 Akt 和 mTOR 信号通路。RARα 的这种非基因组功能很大程度上是配体非依赖性的，控制效应器和调节性 T 细胞亚群的分化。
