The transcriptional repressor AEBP2 is indispensable for the epigenetic control of mimetic thymic epithelial cell differentiation and central self-tolerance induction.

Polycomb repressive complex 2 (PRC2) plays a critical role in gene silencing by catalyzing the addition of H3K27me3 marks to chromatin, a modification essential for maintaining developmental gene repression. In thymic epithelial cells (TECs), PRC2 is required for the differentiation and function of medullary TECs (mTECs) but not cortical TECs. This study investigates the role of AEBP2, an accessory subunit of PRC2, in TEC biology, focusing on its impact on thymus development and central tolerance. We demonstrate that AEBP2 is crucial for the maintenance and differentiation of specific TEC subtypes, including microfold TEC, endoTEC, and Tuft cells. Loss of AEBP2 in TECs results in increased thymic cellularity but impairs the expression of tissue-restricted antigens (TRAs) critical for negative selection of thymocytes. The absence of AEBP2 leads to altered chromatin modifications, with changes in H3K27me3 marks at certain specific TRAs’ loci, suggesting a role in the epigenetic regulation of TRA expression. Furthermore, the loss of AEBP2 correlates with a greater risk of autoimmunity, as evidenced by increased T and B lymphocyte infiltration in peripheral organs. These findings highlight the essential role of AEBP2 in regulating TEC differentiation and self-antigen presentation, providing new insights into the molecular mechanisms of central T cell tolerance.