On the role of AEBP2 in thymus development and function

The ability to distinguish between “Self” and “Non-Self” constitutes the most important functional feature of the immune system. It is primarily instructed for T cells by thymic epithelial cells (TECs) and is made possible by the TEC’s unique capacity to transcribe at the population level nearly all protein coding genes. This expertise, known as promiscuous gene expression (PGE), is in part dependent on the presence of the transcriptional facilitator, Autoimmune Regulator (AIRE) in a subpopulation of medullary TEC (mTEC). H3K27me3 is an important posttranslational modification that epigenetically silences gene expression. A notable exception to this restrictive role of H3K27me3 appears to be the marking of loci that are promiscuously expressed in mTEC to generate a molecular library of self-antigens required for effectively central T cell tolerance induction. H3K27me3 marks are placed by the Polycomb Repressive Complex 2 (PRC2) which includes AEBP2, a well conserved zinc finger protein understood to serve as a targeting protein for the complex. To assess the role of AEBP2 in TEC biology in general and PGE in AIRE+ medullar TEC in particular, mice with a loss of Aebp2 expression in all TEC was analyzed. The absence of AEBP2 in mTECs compromised PGE and resulted in a preferentially decrease of tissue restricted antigen (TRAs) expression dependent on AIRE. A lack of AEBP2 in cortical TECs (cTECs) affected multiple tissue development signaling pathways which may be responsible for the change in cTEC/mTEC ratio at embryonic stage. A lack of AEBP2 in thymocytes affected the early thymocyte development and caused an increased negative selection in both cortex and medulla as well as the post-selection maturation of CD4+ and CD8+ thymocytes. During the investigation of Aebp2 deficient thymocytes via haematopoietic cell transplantation, a robust growth advantage in all haematopoietic lineages was observed. Transcriptome analysis showed an up-regulation of Aurora Kinase A (Aurka) in Aebp2-/- HSCs which may lead to the enhanced proliferation. Taken together, the expression of AEBP2 is essential for the expression of a comprehensive repertoire of self-antigens as well as the development of haematopoietic progenitor cells including thymocytes.