Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Aire is an enigmatic transcription factor that controls immunologic tolerance by inducing, specifically in the thymus, a battery of transcripts encoding proteins not usually encountered until the periphery, thereby promoting negative selection of self-reactive thymocytes and positive selection of regulatory T cells. We document a striking correspondence between those genes induced by Aire and those inhibited by a small-molecule inhibitor of the bromodomain protein Brd4. Aire and Brd4 directly interact, dependent on an orchestrated series of phosphorylation and acetylation events. Aire:Brd4 engagement draws in P-TEFb, mobilizing the transcription and splicing machineries and inducing transcription. Blocking the Aire:Brd4 interaction inhibits negative selection of self-reactive T cells in mice, and point-mutations of Aire that abrogate this association give rise to autoimmune disease.