Function of Aire in central and peripheral immune tolerance

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 transcrip-tional 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 II hi, CD80 lo, CD86 lo, epithelial cell adhesion molecule hi, CD45 lo 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. © 2014 The Japan Society for Clinical Immunology.