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转录剪接优化了胸腺自身抗原库，以抑制自身免疫。

Transcript splicing optimizes the thymic self-antigen repertoire to suppress autoimmunity.

机构信息

Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.

出版信息

J Clin Invest. 2024 Oct 15;134(20):e179612. doi: 10.1172/JCI179612.

DOI:10.1172/JCI179612
PMID:39403924
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11473167/
Abstract

Immunological self-tolerance is established in the thymus by the expression of virtually all self-antigens, including tissue-restricted antigens (TRAs) and cell-type-restricted antigens (CRAs). Despite a wealth of knowledge about the transcriptional regulation of TRA genes, posttranscriptional regulation remains poorly understood. Here, we show that protein arginine methylation plays an essential role in central immune tolerance by maximizing the self-antigen repertoire in medullary thymic epithelial cells (mTECs). Protein arginine methyltransferase-5 (Prmt5) was required for pre-mRNA splicing of certain key genes in tolerance induction, including Aire as well as various genes encoding TRAs. Mice lacking Prmt5 specifically in thymic epithelial cells exhibited an altered thymic T cell selection, leading to the breakdown of immune tolerance accompanied by both autoimmune responses and enhanced antitumor immunity. Thus, arginine methylation and transcript splicing are essential for establishing immune tolerance and may serve as a therapeutic target in autoimmune diseases as well as cancer immunotherapy.

摘要

免疫自身耐受是在胸腺中通过表达几乎所有的自身抗原建立的，包括组织特异性抗原（TRAs）和细胞类型特异性抗原（CRAs）。尽管人们对 TRA 基因的转录调控有了丰富的了解，但对其转录后调控仍知之甚少。在这里，我们表明蛋白质精氨酸甲基化通过最大化髓质胸腺上皮细胞（mTEC）中的自身抗原库，在中枢免疫耐受中发挥着重要作用。蛋白质精氨酸甲基转移酶-5（Prmt5）对于诱导耐受过程中某些关键基因的前体 mRNA 剪接是必需的，包括 Aire 以及各种编码 TRA 的基因。在胸腺上皮细胞中特异性缺失 Prmt5 的小鼠表现出改变的胸腺 T 细胞选择，导致免疫耐受的破坏，伴随着自身免疫反应和增强的抗肿瘤免疫。因此，精氨酸甲基化和转录剪接对于建立免疫耐受至关重要，并且可能成为自身免疫性疾病和癌症免疫治疗的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5b931bd06fcd/jci-134-179612-g113.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5472bffc4c90/jci-134-179612-g107.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/3c4a20c3bc24/jci-134-179612-g108.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/d9f3e9e7e648/jci-134-179612-g109.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/97f2da59a90e/jci-134-179612-g110.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/4755ccfff4bc/jci-134-179612-g111.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5db3635cbe97/jci-134-179612-g112.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5b931bd06fcd/jci-134-179612-g113.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5472bffc4c90/jci-134-179612-g107.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/3c4a20c3bc24/jci-134-179612-g108.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/d9f3e9e7e648/jci-134-179612-g109.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/97f2da59a90e/jci-134-179612-g110.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/4755ccfff4bc/jci-134-179612-g111.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5db3635cbe97/jci-134-179612-g112.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f7c/11473167/5b931bd06fcd/jci-134-179612-g113.jpg

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Cell. 2022 Jul 7;185(14):2542-2558.e18. doi: 10.1016/j.cell.2022.05.018. Epub 2022 Jun 16.
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Instructive Cues of Thymic T Cell Selection.胸腺 T 细胞选择的指示线索。
Annu Rev Immunol. 2022 Apr 26;40:95-119. doi: 10.1146/annurev-immunol-101320-022432.
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Aire-dependent transcripts escape Raver2-induced splice-event inclusion in the thymic epithelium.依赖 Aire 的转录本逃避了胸腺上皮细胞中 Raver2 诱导的剪接事件包含。
可变剪接分析揭示肾上腺素能信号传导是心脏中蛋白质精氨酸甲基转移酶5（PRMT5）的新靶点。
Int J Mol Sci. 2025 Mar 5;26(5):2301. doi: 10.3390/ijms26052301.
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Transcriptional and epigenetic regulation in thymic epithelial cells.胸腺上皮细胞中的转录和表观遗传调控。
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