Journal Article

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

Muro, Ryunosuke, Nakashima, Tomoki, Takayanagi, Hiroshi, Nitta, Takeshi, Okamoto, Kazuo, Asano, Tatsuo, Tsukasaki, Masayuki, Okamura, Tadashi, Nitta, Sachiko, Nakano, Kenta

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: AIRE Protein / Animals / Antigens / Antitumor activity / Arginine / Arginine - genetics / Arginine - immunology / Arginine - metabolism / Autoantigens / Autoantigens - genetics / Autoantigens - immunology / Autoimmune diseases / Autoimmunity / Autoimmunity - immunology / B cells / Cancer immunotherapy / DNA methylation / Epithelial cells / Epithelial Cells - immunology / Epithelial Cells - metabolism / Gene expression / Gene regulation / Genes / Genetic aspects / Genetic transcription / Immune Tolerance - genetics / Immunity (Disease) / Immunological tolerance / Immunology / Immunotherapy / Keratin / Lymphocytes / Lymphocytes T / Medical research / Medicine, Experimental / Messenger RNA / Methylation / Mice / Mice, Knockout / Physiological aspects / Physiology / Post-transcription / Protein arginine methyltransferase / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - immunology / Proteins / RNA splicing / RNA Splicing - immunology / Scientific equipment and supplies industry / Self Tolerance - genetics / Self Tolerance - immunology / Signal transduction / Splicing / T cell receptors / T cells / Therapeutic targets / Thymus / Thymus gland / Thymus Gland - immunology / Transcription Factors - genetics / Transcription Factors - immunology / Transcription Factors - metabolism