Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance

Abstract

Although some advances have been made in understanding the molecular regulation of mTEC development, the role of epigenetic regulators in the development and maturation of mTEC is poorly understood. Here, using the TEC-specific Sirt6 knockout mice, we found the deacetylase Sirtuin 6 (Sirt6) is essential for the development of functionally competent mTECs. First of all, TEC-specific Sirt6 deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of Sirt6-deficient mTECs. Secondly, Sirt6 deficiency specifically accelerates the differentiation of mTECs from CD80–Aire– immature population to CD80+Aire– intermediate mature population by promoting the expression of Spib. Finally, Sirt6 ablation in TECs markedly interferes the proper expression of tissue-restricted antigens (TRAs) and impairs the development of thymocytes and nTreg cells. In addition, TEC conditional knockout of Sirt6 results in severe autoimmune disease manifested by reduced body weight, the infiltration of lymphocytes and the presence of autoantibodies. Collectively, this study reveals that the expression of epigenetic regulator Sirt6 in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.

Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development

“…Consistent with our previous reports 35 , the Foxn1-Cre mouse strain (a gift from Dr. Yu Zhang) 54 , 55 was crossed with Sirt6 loxp/loxp mouse strain (a gift from Dr. Zhenyu Ju) 56 , 57 to generate the Foxn1-Cre Sirt6 loxp/loxp mice and Foxn1-Cre negative littermate controls. Mice were maintained in the Institute of Zoology, Chinese Academy of Sciences (IOZ, CAS) specific pathogen-free conditions and approved by the Animal Ethics Committee of Institute of Zoology, Beijing, China.…”

“…Previous studies have proven that SIRT6, as a key chromatin regulator, remodels chromatin by promoting chromatin relaxation, although it has diverse biological functions, such as genome stability, glucose metabolism, and tumor suppression, through multiple pathways 29 – 34 . We, therefore, bred Foxn1-Cre mice with Sirt6 flox/flox mice to obtain TEC-specific deletion of Sirt6 mice as reported recently 35 . TEC-specific Sirt6 deletion reduced the cell number of mTECs with an accelerated differentiation of CD80 - Aire - immature mTECs to CD80 + Aire - intermediate mature mTECs by promoting Spib expression 35 .…”

“…We, therefore, bred Foxn1-Cre mice with Sirt6 flox/flox mice to obtain TEC-specific deletion of Sirt6 mice as reported recently 35 . TEC-specific Sirt6 deletion reduced the cell number of mTECs with an accelerated differentiation of CD80 - Aire - immature mTECs to CD80 + Aire - intermediate mature mTECs by promoting Spib expression 35 . However, we observed that the taste transduction signal pathway and taste-related genes were significantly downregulated in Sirt6 -deficient mTECs, while endocytosis, NF-κB, and other pathways were enhanced, as detected by RNA-seq analysis (Fig.…”

“…4 and ref. 35 ). The integrated scATAC-seq data did not reveal the developmental trajectory of thymic tuft cells, which was consistent with the WT scATAC-seq results mentioned above.…”

Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy

“…Accordingly, H&E staining demonstrates more severe lymphocytic infiltration in multiple organs, including the kidney, lung, and liver. It is suggested that the establishment of central immune tolerance is disrupted after SIRT6 deletion [ 31 ]. Collectively, the expression of epigenetic regulator SIRT6 in TECs is responsible for the development and differentiation of the mTECs lines (Fig.…”