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

Liang Tan,Yong Zhao,Tong Lei,Huiting Su,Jiayu Zhang,Qian Zhang,Yifang Chen,Xue Dong,Zhanfeng Liang,Zhaoqi Zhang

doi:10.3389/fcell.2021.655552

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.

Highlights

As a primary lymphoid organ, thymus plays an indispensable role in the establishment of central immune tolerance (Anderson and Takahama, 2012; Abramson and Anderson, 2017)
The morphological analysis showed that thymic medullary region decreased significantly while the cortical region had no obvious change after Sirtuin 6 (Sirt6) ablation (Figures 1C,D)
The morphology of thymus in 8-month-old Sirt6 cKO mice showed no obvious signs of aging and the cortico-medullary junctions was integrated as assessed by H&E staining and Masson staining (Supplementary Figures 2C,D)

Summary

Introduction

As a primary lymphoid organ, thymus plays an indispensable role in the establishment of central immune tolerance (Anderson and Takahama, 2012; Abramson and Anderson, 2017). Compared with immature mTECs, functional mature mTECs act as the antigen present cell characterized by high expression of CD80, MHC class II (MHC II), and Aire (Kyewski and Klein, 2006; Klein et al, 2009; Anderson and Su, 2016) The expression of these molecules by mTECs is indispensable for thymocytes negative selection (Kadouri et al, 2020). Mature mTECs mediate the deletion of autoreactive T cells and promote the development of natural regulatory T cell (nTreg) by expressing tissue-restricted antigens (TRAs), which is essential for the establishment of central immune tolerance (Aschenbrenner et al, 2007; Cowan et al, 2013; Malhotra et al, 2016; Lebel et al, 2020). The epigenetic regulation of other Sirtuins family members in TEC development is not clear

Methods

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Conclusion