Abstract Transposable elements (TE) are repetitive sequences representing ∼45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTEC). In this study, we investigated the role of transposable elements (TE), which are highly expressed by medullary thymic epithelial cells (mTEC), on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TEs interact with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and RELB) and generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that lead to the formation of dsRNA, triggering RIG-I and MDA5 signaling and explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study illustrates the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that the orchestration of TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
