Abstract
The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression.
Highlights
The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells
This ectopic expression of tissue-specific self-antigens (TSAs) largely depends on the transcriptional regulator Aire[5,6,7,8], which is expressed in mature mTECs9–11
Our findings indicate that Aire protein expression is tightly controlled through two discrete steps, intron retention and its relief, the latter of which involves the enzymatic activity of Jmjd[6]
Summary
The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. Jmjd[6] deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd[6], resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. We show that Jmjd[6] plays a key role in induction of central tolerance by controlling Aire expression in mTECs. Jmjd[6] deficiency did not affect abundance of Aire transcript, the intron 2 of Aire gene was not effectively spliced out in the absence of Jmjd[6], owing to the unique 30 splice site sequence. Our findings indicate that Aire protein expression is tightly controlled through two discrete steps, intron retention and its relief, the latter of which involves the enzymatic activity of Jmjd[6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
