Abstract
The autoimmune regulator (Aire)-directed ectopic expression of tissue-specific antigens (TSAs) by mature medullary thymic epithelial cells (mTECs) has been viewed as an essential mechanism in the induction of central tolerance. Recent data suggest that the survival of mTECs extends beyond the Aire+ cell population to form the post-Aire mTEC population and Hassall’s corpuscles (HCs). The nature and function of these post-Aire epithelial cells and structures, however, have remained unidentified. In this study, we characterized in detail the end-stage development of mTECs and HCs in both Aire-sufficient and Aire-deficient mice. In addition, using a transgenic mouse model in which the LacZ reporter gene is under the control of the endogenous Aire promoter, we purified and analyzed the post-Aire mTECs to characterize their function. We showed that the end-stage maturation of mTECs closely resembles that of keratinocytes and that the lack of Aire results in a marked block of mTEC differentiation, which is partially overcome by ligands for RANK and CD40. We also provide evidence that, during mTEC development, Aire is expressed only once and during a limited 1–2 day period. The following loss of Aire expression is accompanied by a quick downregulation of MHC class II and CD80, and of most of the Aire-dependent and Aire-independent TSAs, with the exception of keratinocyte-specific genes. In the final stage of maturation, the mTECs lose their nuclei to become HCs and specifically express desmogleins (DGs) 1 and 3, which, via cross-presentation by APCs, may contribute to tolerance against these pemphigus vulgaris-related TSAs.
Highlights
The thymus is the primary lymphoid organ involved in the development of thymocytes and has a fundamental role in establishing immune tolerance (Gallegos and Bevan, 2006)
We showed that the end-stage maturation of medullary thymic epithelial cells (mTECs) closely resembles that of keratinocytes and that the lack of autoimmune regulator (Aire) results in a marked block of mTEC differentiation, which is partially overcome by ligands for RANK and CD40
CHARACTERIZATION OF END-STAGE mTECs/Hassall’s corpuscles (HCs) BY EPIDERMAL MARKERS IN MICE In order to characterize the final stages of mTEC maturation/HC development in comparison with the maturation of keratinocytes, we evaluated the expression of four (CK6, CK10, involucrin, lympho-epithelial Kazal-type related inhibitor (LEKTI)) epidermal cell markers in mouse skin vs. thymus (Figure 1)
Summary
The thymus is the primary lymphoid organ involved in the development of thymocytes and has a fundamental role in establishing immune tolerance (Gallegos and Bevan, 2006). An essential feature in the induction of central tolerance is the promiscuous expression of tissue-specific antigens (TSAs) by terminally differentiated medullary thymic epithelial cells (mTECs; Derbinski et al, 2001). The pool of these mTEC-expressed TSAs is extremely diverse and covers most of the putative autoantigen targets of experimental animal models and of human autoimmune diseases (Kyewski and Derbinski, 2004). The lack of Aire in a mouse model is accompanied by the downregulation of more than a thousand TSAs in the mTECs resulting in multiple defects in thymocyte development including impaired negative selection (Liston et al, 2003), Treg production (Kekalainen et al, 2007; Pomie et al, 2011), and CD4SP cell maturation (Li et al, 2007). The main outcome is autoimmunity against multiple tissues, described both in Aire-deficient mice as well as in AIRE-deficient (autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy) patients (Anderson et al, 2002; Peterson and Peltonen, 2005)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
