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

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Central immune tolerance is established in the thymus via self-antigen expression.
• Posttranscriptional regulation of self-antigens, particularly tissue-restricted antigens (TRAs), is not well understood.
• Understanding these mechanisms is key to addressing autoimmune diseases and cancer.

Purpose of the Study:

• To investigate the role of protein arginine methylation in central immune tolerance.
• To elucidate the function of Protein arginine methyltransferase-5 (Prmt5) in thymic epithelial cells (mTECs).
• To explore the impact of Prmt5-mediated regulation on self-antigen presentation and T cell selection.

Main Methods:

• Studied the role of Prmt5 in pre-mRNA splicing of key genes involved in tolerance.
• Generated mice with Prmt5 deficiency specifically in thymic epithelial cells.
• Analyzed thymic T cell selection and immune responses in these mice.

Main Results:

• Protein arginine methylation, via Prmt5, is essential for maximizing the self-antigen repertoire in mTECs.
• Prmt5 regulates pre-mRNA splicing of Aire and TRA genes critical for tolerance.
• Loss of Prmt5 in mTECs leads to impaired T cell selection, autoimmune disease, and enhanced anti-tumor immunity.

Conclusions:

• Arginine methylation and transcript splicing are vital for establishing immune tolerance.
• Prmt5-mediated regulation represents a potential therapeutic target for autoimmune disorders and cancer immunotherapy.