Control of central and peripheral tolerance by Aire

Abstract

The negative selection of self-reactive thymocytes depends on the expression of tissue-specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent, endogenous tissue-specific antigens remains to be determined.

Fig. 1. Aire⁺ mTECs may represent a terminally differentiated TEC population

mTECs expressing low levels of CD80 and MHC class II (mTEC^lo) appear to differentiate into mTECs expressing high levels of both CD80 and MHC class II (mTEC^hi). Aire expression (represented by depiction of its characteristic histological nuclear speckling) is restricted to a non-dividing subset of the mTEC^hi subset.

Fig. 2. Central and peripheral Aire expression promotes tolerance through complementary mechanisms

Central Aire expression is most important during a perinatal window, and promotes tolerance through negative selection against tissue-specific antigens within the thymus. Peripheral Aire expression is likely to promote tolerance throughout life, and may induce deletional tolerance, Foxp3⁺ regulatory T cells, or anergy through the expression of a distinct set of peripheral tissue-specific antigens. The lack of CD80 and CD86 on peripheral eTACs is likely to be an important component of their tolerance induction.