美国拉霍亚免疫研究所Hilde Cheroutre和Samuel A. Myers研究组合作发现，一个由核外和核RA连接维甲酸受体α (RARα)控制的调控回路决定了T细胞的活化和功能。这一研究成果于2023年8月18日发表在国际顶尖学术期刊《免疫》上。

他们研究了RARα是否会发挥转录调控以外的作用。RARα核异构体的特异性缺失揭示了T细胞细胞质中的RARα异构体。核外RARα在TCR刺激下迅速磷酸化并被募集到TCR信号体。RA干扰核外RARα信号，导致TCR激活次优，同时增强FOXP3+调节性T细胞转化。TCR激活诱导CRABP2的表达，使RA易位到细胞核。缺失Crabp2导致细胞质中RA增加，干扰信号体- RARα，导致抗病原体免疫功能受损，抑制自身免疫性疾病。

他们的研究结果强调了亚细胞RA/RARα信号在T细胞中的重要性，并确定核外RARα是TCR信号体的一个组成部分和免疫反应的决定因素。

研究人员表示，RA连接RARα可促进与免疫激活和耐受相关的多种转录程序，但遗传缺失方法提示RARα对TCR信号传导的影响。

附：英文原文

Title: A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function

Author: Alexandre Larange, Ikuo Takazawa, Kiyokazu Kakugawa, Nicolas Thiault, SooMun Ngoi, Meagan E. Olive, Hitoshi Iwaya, Laetitia Seguin, Ildefonso Vicente-Suarez, Stephane Becart, Greet Verstichel, Ann Balancio, Amnon Altman, John T. Chang, Ichiro Taniuchi, Bjorn Lillemeier, Mitchell Kronenberg, Samuel A. Myers, Hilde Cheroutre

Issue&Volume: 2023-08-18

Abstract: Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptionalprograms associated with immune activation and tolerance, but genetic deletion approachessuggest the impact of RARα on TCR signaling. Here, we examined whether RARα wouldexert roles beyond transcriptional regulation. Specific deletion of the nuclear isoformof RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα wasrapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome.RA interfered with extranuclear RARα signaling, causing suboptimal TCR activationwhile enhancing FOXP3+ regulatory T cell conversion. TCR activation induced the expression of CRABP2, whichtranslocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resultingin impaired anti-pathogen immunity and suppressed autoimmune disease. Our findingsunderscore the significance of subcellular RA/RARα signaling in T cells and identifyextranuclear RARα as a component of the TCR signalosome and a determinant of immuneresponses.

DOI: 10.1016/j.immuni.2023.07.017

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00330-8