Indispensable epigenetic control of thymic epithelial cell development and function by Polycomb Repressive Complex 2

Thymic T cell development and T cell antigen receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TECs). These cells rely for their development and function on the correct placement of post-translational histone modifications. The repressive H3K27me3 mark is catalyzed by the holoenzyme Polycomb Repressive Complex 2 (PRC2). Mice with a TEC-targeted deficiency of PRC2 are differentially affected in their TEC lineage development establishing a novel differentiation path that progressively off-sets the shortage of canonical medullary TEC. The resultant hypoplastic thymus is severely compromised in its ability present antigen and to select a repertoire of T cells with normal effector and regulatory functions. A heightened peripheral activation of regulatory T cells, however, prevents the occurrence of overt autoimmunity in these mice. Single cell RNA-seq, bulk RNA-seq and ChIP-seq on thymic epithelial cell subsets (cTEC and mTEChi) from wild-type and Eedfl/fl::ZsGreen::beta5tCre mice