T-regulatory cells require Sin3a for stable expression of Foxp3

• Published in: Frontiers in immunology 2024-08, Vol.15, p.1444937
• Main Authors: Christensen, Lanette M, Akimova, Tatiana, Wang, Liqing, Han, Rongxiang, Samanta, Arabinda, Di Giorgio, Eros, Hancock, Wayne W
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; demethylation; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXP3+ Treg; Gene Expression Regulation; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Repressor Proteins - genetics; Repressor Proteins - metabolism; Sin3 Histone Deacetylase and Corepressor Complex - genetics; SIN3A; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-regulatory cell; transcription regulation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1444937

Histone deacetylases 1 and 2 play a major role in the transcriptional regulation of T-regulatory (Treg) cells via interactions with a myriad of coregulatory factors. Sin3a has been well established as a Hdac1/2 cofactor, while its role within Tregs has not been established. In this study, the effects of conditional deletion of Sin3a within Foxp3+ Tregs were evaluated. Developmental deletion of Sin3a from Foxp3+ Tregs resulted in the rapid onset of fatal autoimmunity. Treg numbers were greatly reduced, while residual Tregs had impaired suppressive function. Mice also showed effector T-cell activation, autoantibody production, and widespread tissue injury. Mechanistically, Sin3a deletion resulted in decreased transcription of with a complete lack of CNS2 CpG demethylation. In addition, Foxp3 protein stability was impaired with an increased ex-Treg population. Thus, Sin3a plays a critical role in the maintenance of Treg identity and function and is essential for the expression and stability of Foxp3.