Post-Aire Maturation of Thymic Medullary Epithelial Cells Involves Selective Expression of Keratinocyte-Specific Autoantigens

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

Lymphopenia-induced proliferation in Aire-deficient mice helps to explain their autoimmunity and differences from human patients

Studies on autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and its mouse model – both caused by mutant AIRE – have greatly advanced the under-standing of thymic processes that generate a self-tolerant T-cell repertoire. Much is now known about the molecular mechanisms by which AIRE induces tissue-specific antigen expression in thymic epithelium, and how this leads to negative selection of autoreactive thymocytes. However, we still do not understand the processes that lead to the activation of any infrequent naïve auto-reactive T-cells exported by AIRE-deficient thymi. Also, the striking phenotypic differences between APECED and its mouse models have puzzled researchers for years. The aim of this review is to suggest explanations for some of these unanswered questions, based on a fresh view of published experiments. We bring evidence that autoreactive T-cells can be activated by prolonged neonatal lymphopenia that naturally develops in young Aire-deficient mice due to delayed export of mature thymocytes. Lymphopenia induced proliferation (LIP) fills the empty space favoring autoreactive T cells. This leads to lymphocyte infiltration in similar tissues as seen in day 3 thymectomised animals. LIP turns uncontrolled in Aire–/– crosses with other model mice with defects in genes responsible for anergy induction and Treg responsiveness, or defects in TCR signaling in combination with impaired function of homeostatic cytokines. In APECED patients LIP is probably not among the factors that participate in naïve autoreactive T cell activation as humans are born with more mature immune system in comparison to mice. We suggest that human AIRE-deficiency presents with different phenotype due to additional precipitating factors on top of deficient negative selection of tissue-specific thymocytes