Role of polycomb repressive complex 2 in thymic epithelial development and function

Abstract

Thymic epithelial cells (TEC) make up a majority of the thymic stroma and can be classified into cortical (c) and medullary (m) compartment. TEC are responsible for generating a self-tolerant T cell repertoire and thus potentially self-reactive thymocytes are induced to undergo apoptosis in the process termed negative selection. For this purpose, TEC express over 19,000 protein-encoding genes to represent almost the entire repertoire of protein-encoded antigens of the host. Many of these genes are typically expressed only in specific organs and are referred to as tissue-restricted antigens (TRA). The autoimmune regulator (Aire) facilitates the expression of a subset of TRA and these Aire-regulated TRA occupy chromatin regions enriched with the trimethylation of 27th lysine on histone 3 (H3K27me3), an epigenetic mark is catalysed by the methyltransferase activity of Polycomb Repressive Complex 2 (PRC2). However, the physiological significance of H3K27me3 in TEC biology remains to be elucidated. To address this issue, mice with TEC-targeted PRC2 deficiency were generated. These mice displayed severely hypocellular thymi but yet maintained intact tissue architecture and total TEC cellularity. Within the TEC population, mTEC cellularity was drastically reduced and the maturation of mTEC was also hindered. Furthermore, the decrease in number of early T lineage progenitors recruited correlated with the reduced expression of chemokines by the cTEC. The deficiency of PRC2 in TEC also interfered with efficiency of negative selection and Treg production. Single cell transcriptome and flow cytometric data demonstrated that the deficiency of PRC2 activity also provokes mTEC development along a novel lineage differentiation path. Taken together, these data provide experimental proof that PRC2 plays crucial roles in the regulation of TEC differentiation and the capacity to carry out negative selection.