title: Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire.
abstract: Expression of autoimmune regulator (Aire) by thymic medullary epithelial cells (MECs) is critical for central tolerance of self. To explore the mechanism by which such a rare cell population imposes tolerance on the large repertoire of differentiating thymocytes, we examined the proliferation and turnover of Aire(+) and Aire(-) MEC subsets through flow cytometric analysis of 5-bromo-2'deoxyuridine (BrdU) incorporation. The Aire(+) MEC subset was almost entirely postmitotic and derived from cycling Aire(-) precursors. Experiments using reaggregate thymic organ cultures revealed the presence of such precursors among Aire(-) MECs expressing low levels of major histocompatibility complex class II and CD80. The kinetics of BrdU decay showed the Aire(+) population to have a high turnover. Aire did not have a direct impact on the division of MECs in vitro or in vivo but, rather, induced their apoptosis. We argue that these properties strongly favor a "terminal differentiation" model for Aire function in MECs, placing strict temporal limits on the operation of any individual Aire(+) MEC in central tolerance induction. We further speculate that the speedy apoptosis of Aire-expressing MECs may be a mechanism to promote cross-presentation of the array of peripheral-tissue antigens they produce.
authors.affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gray
authors.forename: Jakub
authors.initials: J
authors.lastname: Abramson
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004247:DNA / Q000032:analysis / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D010641:Phenotype; D013950:Thymus Gland / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D004247:DNA; D014157:Transcription Factors; D000096927:AIRE Protein