Transcript splicing optimizes the thymic self-antigen repertoire to suppress autoimmunity
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.
Authors
- Masayuki Tsukasaki (ORCID: https://orcid.org/0000-0001-7278-9643)
- Tatsuo Asano (ORCID: https://orcid.org/0000-0003-0669-8123)
- Hiroshi Takayanagi (ORCID: https://orcid.org/0000-0002-1462-4127)
- Kenta Nakano (ORCID: https://orcid.org/0000-0003-2617-1468)
- Takeshi Nitta (ORCID: https://orcid.org/0000-0003-2384-3062)
- Sachiko Nitta
- Tomoki Nakashima (ORCID: https://orcid.org/0000-0001-6779-8617)
- Ryunosuke Muro
- Kazuo Okamoto (ORCID: https://orcid.org/0000-0001-5855-5357)
- Tadashi Okamura (ORCID: https://orcid.org/0000-0001-8457-1561)
Institutions
- Kanazawa University (JP)
- Tokyo Medical and Dental University (JP)
- Tokyo University of Information Sciences (JP)
- National Center for Global Health and Medicine (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1172/jci179612
- Citations
- 4
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.96
Funders
- Japan Agency for Medical Research and Development
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- University of Tokyo
- Astellas Pharma
- University of Tokushima
- Astellas Foundation for Research on Metabolic Disorders
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology