Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 204, Issue 11, Pages 2521-2528Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20070795
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Funding
- NIDDK NIH HHS [R01 DK60027, R01 DK060027] Funding Source: Medline
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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.
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