Abstract
Aire impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells, thereby controlling the repertoire of self-antigens encountered by differentiating thymocytes. Both humans and mice lacking Aire develop multiorgan autoimmunity. Currently, there are few molecular details on how Aire performs this crucial function. The more amino-terminal of its two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by "reading" the methylation status of a particular lysine residue of histone-3, a process that does not depend on the more carboxyl-terminal PHD-2. This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice. PHD2 was required for Aire to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing; it also was not required for Aire's nuclear translocation or regional distribution. PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcriptome and so was crucial for effective central tolerance induction. Thus, Aire's two PHDs seem to play distinct roles in the scenario by which it assures immunological tolerance.