Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.
Immunity. 2023 Sep 12;56(9):2054-2069.e10. doi: 10.1016/j.immuni.2023.07.017. Epub 2023 Aug 18.
Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome. RA interfered with extranuclear RARα signaling, causing suboptimal TCR activation while enhancing FOXP3 regulatory T cell conversion. TCR activation induced the expression of CRABP2, which translocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resulting in impaired anti-pathogen immunity and suppressed autoimmune disease. Our findings underscore the significance of subcellular RA/RARα signaling in T cells and identify extranuclear RARα as a component of the TCR signalosome and a determinant of immune responses.
维甲酸受体α (RARα) 通过 RA 的结合促进与免疫激活和耐受相关的多种转录程序，但基因缺失方法表明 RARα 对 TCR 信号的影响。在这里，我们研究了 RARα 是否会发挥超出转录调控的作用。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。TCR 刺激后，核外 RARα 迅速磷酸化，并募集到 TCR 信号体。RA 干扰核外 RARα 信号，导致 TCR 激活不足，同时增强 FOXP3 调节性 T 细胞的转化。TCR 激活诱导 CRABP2 的表达，将 RA 转运到细胞核。Crabp2 的缺失导致细胞质中 RA 增加，并干扰信号体-RARα，导致抗病原体免疫受损和自身免疫性疾病抑制。我们的发现强调了细胞内 RA/RARα 信号在 T 细胞中的重要性，并确定核外 RARα 是 TCR 信号体的组成部分和免疫反应的决定因素。
