AIRE in context: Leveraging chromatin plasticity to trigger ectopic gene expression*

Abstract The emergence of antigen receptor diversity in clonotypic lymphocytes drove the evolution of a novel gene, Aire , that enabled the adaptive immune system to discriminate foreign invaders from self‐constituents. AIRE functions in the epithelial cells of the thymus to express genes highly restricted to alternative cell lineages. This somatic plasticity facilitates the selection of a balanced repertoire of T cells that protects the host from harmful self‐reactive clones, yet maintains a wide range of affinities for virtually any foreign antigen. Here, we review the latest understanding of AIRE’s molecular actions with a focus on its interplay with chromatin. We argue that AIRE is a multi‐valent chromatin effector that acts late in the transcription cycle to modulate the activity of previously poised non‐coding regulatory elements of tissue‐specific genes. We postulate a role for chromatin instability—caused in part by ATP‐dependent chromatin remodeling—that variably sets the scope of the accessible landscape on which AIRE can act. We highlight AIRE’s intrinsic repressive function and its relevance in providing feedback control. We synthesize these recent advances into a putative model for the mechanistic modes by which AIRE triggers ectopic transcription for immune repertoire selection.