Lineage Tracing and Cell Ablation Identify a Post-Aire-Expressing Thymic Epithelial Cell Population

• Published in: Cell reports (Cambridge) Vol. 5; no. 1; pp. 166 - 179
• Main Authors: Metzger, Todd C., Khan, Imran S., Gardner, James M., Mouchess, Maria L., Johannes, Kellsey P., Krawisz, Anna K., Skrzypczynska, Katarzyna M., Anderson, Mark S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2013; Elsevier
• Subjects: Animals; Cell Differentiation - physiology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Female; Humans; Mice; Mice, Transgenic; Signal Transduction; Thymocytes - cytology; Thymocytes - metabolism; Thymus Gland - cytology; Thymus Gland - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.08.038

Thymic epithelial cells in the medulla (mTECs) play a critical role in enforcing central tolerance through expression and presentation of tissue-specific antigens (TSAs) and deletion of autoreactive thymocytes. TSA expression requires autoimmune regulator (Aire), a transcriptional activator present in a subset of mTECs characterized by high CD80 and major histocompatibility complex II expression and a lack of potential for differentiation or proliferation. Here, using an Aire-DTR transgenic line, we show that short-term ablation specifically targets Aire+ mTECs, which quickly undergo RANK-dependent recovery. Repeated ablation also affects Aire− mTECs, and using an inducible Aire-Cre fate-mapping system, we find that this results from the loss of a subset of mTECs that showed prior expression of Aire, maintains intermediate TSA expression, and preferentially migrates toward the center of the medulla. These results clearly identify a distinct stage of mTEC development and underscore the diversity of mTECs that play a key role in maintaining tolerance. [Display omitted] •Aire-DTR mice allow ablation of Aire+ medullary thymic epithelial cells (mTECs)•Repeated ablation in Aire-DTR mice leads to loss of mTEC subsets•Fate mapping reveals a large population of post-Aire mTECs•Post-Aire mTECs retain intermediate TSA expression and lose maturation markers In this study, Anderson and colleagues investigate the recovery and developmental potential of Aire+ thymic epithelial cells (TECs), a cell population with unique roles in limiting self-reactivity of developing T cells. The authors find that this population is capable of rapid recovery following targeted ablation and that such ablation leads to loss of tolerance to self. The authors also find that Aire+ TECs progress to a terminal Aire− stage, which may have a unique role in driving central tolerance.