Mutations of the Autoimmune Regulator (Aire) were first identified as the cause of a multi-organ autoimmune syndrome, APS-1, in 1997, and it has since become appreciated that Aire normally functions to prevent autoimmunity by facilitating self tolerance to peripheral antigens. Specifically, Aire is expressed at high levels in the medullary epithelial cells in the thymus, the site of T cell development, where it drives expression of otherwise silent, tissue-specific antigens (TSAs) like insulin, resulting in central tolerance towards TSAs. Here, we describe the pattern of Aire expression among medullary thymic epithelial cells (mTEC) and the potential of Aire+ mTECs to recover from targeted ablation. We demonstrate that Aire+ mTECs have a remarkable ability to quickly recover from targeted ablation in a manner that depends on signaling through the TNF superfamily member RANK. We also show that Aire+ mTECs harbor a previously unappreciated potential to reduce Aire and MHCII expression and migrate towards the center of the thymic medulla while maintaining TSA expression. In addition to its role in the thymus, Aire expression has also recently been identified in population of extrathymic Aire-expressing cells (eTACs) residing in the peripheral lymphoid tissues. We address the ability of eTACs to contribute to CD4+ T cell tolerance, and find that eTACs are capable of inducing anergy of autoreactive T through a signaling pathway that depends in part on low expression of costimulatory CD80 and CD86 molecules by eTACs. Finally, we identify eTACs as a non-conventional component of the classical dendritic cell lineage, suggesting that they can be efficiently expanded for future functional studies and potentially for therapeutic induction of tolerance.
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