LAUSR

Aire allows medullary thymic epithelial cells (mTECs) to express and present a large number of self‐antigens for central tolerance. Although mTECs express a high diversity of self‐antigen splice isoforms, the extent and regulation of alternative splicing events (ASEs) in their transcripts, notably in those induced by Aire, is unknown. In contrast to Aire‐neutral genes, we find that transcripts of Aire‐sensitive genes show only a low number of ASEs in mTECs, with about a quarter present in peripheral tissues excluded from the thymus. We identify Raver2, as a splicing‐related factor overexpressed in mTECs and dependent on H3K36me3 marks, that promotes ASEs in transcripts of Aire‐neutral genes, leaving Aire‐sensitive ones unaffected. H3K36me3 profiling reveals its depletion at Aire‐sensitive genes and supports a mechanism that is preceding Aire expression leading to transcripts of Aire‐sensitive genes with low ASEs that escape Raver2‐induced alternative splicing. The lack of ASEs in Aire‐induced transcripts would result in an incomplete Aire‐dependent negative selection of autoreactive T cells, thus highlighting the need of complementary tolerance mechanisms to prevent activation of these cells in the periphery.