Abstract
Negative selection induces central tolerance in which self-reactive T cells are deleted by medullary thymic epithelial cells (mTECs) to prevent autoimmunity. The transcriptional factor, autoimmune regulator (Aire), controls the expression of tissue-specific antigens (TSAs) by mTECs for negative selection. The mechanisms by which Aire targets loci which encode TSAs are unknown in detail; recently, however, the ATF7ip-MBD1 complex was identified as an Aire-interacting transcriptional protein complex required for its targeting the loci. Lineage tracing of Aire+ mTECs identified that mTECs have a post-Aire stage during the development, where they lost maturation markers but maintained intermediate TSA expression, and Aire is required for the terminal differentiation of mTEC's. Extrathymic Aire-expressing cells (eTACs) are identified in murine and human secondary lymphoid organs. eTACs express major histocompatibility complex class IIhi, CD80lo, CD86lo, epithelial cell adhesion moleculehi, CD45lo bone marrow-derived peripheral antigen-presenting cell population, which is distinct from mTECs and dendritic cells. They can induce activation-induced cell death of self-reactive CD8+ T cells and unresponsiveness of self-reactive CD4+ T cells through a mechanism that does not require regulatory T cells, suggesting that peripheral Aire plays a complementary role for central tolerance.
