Rapid chromatin repression by Aire provides precise control of immune tolerance

Aire mediates the expression of tissue-specific antigens in thymic epithelial cells to remove dangerous self-reactive T lymphocytes. However, the mechanism that allows expression of tissue-specific genes at levels that prevent harm is unknown. Here we show that Brg1 generates accessibility at tissue-specific loci to impose central tolerance. We found that Aire harbors an intrinsic repressive function that restricts chromatin accessibility and opposes Brg1 across the genome. Aire exerted this repressive influence within minutes upon recruitment to chromatin and restrained the amplitude of active transcription. Autoimmune mutations that impair Aire-induced activation also impair the its repression function, indicating dual roles for Aire. Together, Brg1 and Aire fine-tune the expression of tissue-specific genes at levels that prevent toxicity, yet promote immune tolerance.