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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\u2010reactive clones, yet maintains a wide range of affinities for virtually any foreign antigen. Here, we review the latest understanding of AIRE\u2019s molecular actions with a focus on its interplay with chromatin. We argue that AIRE is a multi\u2010valent chromatin effector that acts late in the transcription cycle to modulate the activity of previously poised non\u2010coding regulatory elements of tissue\u2010specific genes. We postulate a role for chromatin instability\u2014caused in part by ATP\u2010dependent chromatin remodeling\u2014that variably sets the scope of the accessible landscape on which AIRE can act. We highlight AIRE\u2019s 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.<\/jats:p>","DOI":"10.1111\/imr.13026","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T04:35:11Z","timestamp":1632198911000},"page":"59-76","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["AIRE in context: Leveraging chromatin plasticity to trigger ectopic gene expression*"],"prefix":"10.1111","volume":"305","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2731-407X","authenticated-orcid":false,"given":"Caroline","family":"Kaiser","sequence":"first","affiliation":[{"name":"Department of Pathology University of Chicago Chicago IL USA"},{"name":"Department of Human Genetics University of Chicago Chicago IL 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