A transcriptomic census reveals that Rbfox contributes to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus

Abstract

Thymic epithelial cells (TEC) guide selection of a T-cell repertoire that is reactive to pathogens but tolerant to self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire by TEC, the extent to which these cells reproduce peripheral isoform structures is unknown. We performed a transcriptomic investigation of transcript structures and splicing factor expression in medullary TEC and 21 peripheral tissues. Our results indicate that TEC re-use a small number of peripheral splicing factors to recreate a limited subset of the peripheral splice isoform repertoire. We found, for example, that TEC lacked both neuronal micro-exons and the splicing factor, Srrm4, which promotes their inclusion. We demonstrate a functional role for the Rbfox splicing factors in promoting medullary TEC development and the alternative splicing of promiscuously expressed genes. Our findings have implications for understanding autoimmune diseases and the development of antigen-specific immunotherapies.

The contribution of thymic tolerance to central nervous system autoimmunity

“…One characteristic that distinguishes CNS-specific TRAs from those found in other organs, is an enrichment for micro-exons: the expression of exonic sequences ≤ 30 basepairs in length [60,61]. Relatively little is understood regarding the expression of micro-exon-containing genes within mTEC, but recent research suggests that micro-exons are poorly represented within the thymus with or without the expression of AIRE [62]. CNS antigens are also known to undergo post-translational modification [63].…”