AIRE transcriptional condensates in central tolerance: a multiscale mechanistic perspective

Abstract

Autoimmune regulator (AIRE) enables medullary thymic epithelial cells (mTECs) to express a broad but selective repertoire of tissue-restricted antigens (TRAs), thereby supporting central T-cell tolerance. Recent studies showing that AIRE forms transcriptionally active condensates provide a framework for understanding how chromatin recognition, enhancer-associated cofactor recruitment, three-dimensional genome organization and transcriptional elongation are coordinated during TRA induction. In this view, sparse TRA expression reflects the low probability that a given locus reaches a permissive chromatin and cofactor state, whereas high output may result from local enrichment of BRD4, P-TEFb, Mediator-associated co-activators and elongation machinery after activation. Recent findings on thymic mimetic cells, human thymic spatial organization and peripheral RORγt-associated antigen-presenting cells are discussed as related contexts, with particular attention to the current lack of direct evidence for mTEC-like AIRE condensate mechanisms outside mTECs. Together, these studies place AIRE condensates within a broader regulatory landscape of chromatin gating, transcriptional kinetics and mTEC state diversity.