Thymosin α1: burying secrets in the thymus

Thymosin α1 (Tα1), an epithelial cell (EC)-derived cytokine, has the strong ability to modulate signals delivered through innate immune receptors on dendritic cells (DCs), thus instructing the initiation of appropriate immune responses to T cells. In its ability to activate indoleamine 2,3-dioxygenase 1-dependent tolerogenic programs in DCs, Tα1 pivotally contributes to the maintenance of self-tolerance by regulating the function of regulatory T (Treg) cells. How Tα1 may contribute to the Treg cell ontogeny is not known. The transcriptional regulator autoimmune regulator (AIRE) is known to control central and peripheral tolerance. AIRE is highly expressed in thymic medullary ECs where it controls the ectopic expression of tissue restricted antigens for negative selection. The absence of AIRE-induced tissue-specific antigens 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 may play a complementary role. We have addressed the possible relationship between AIRE and Tα1 and discovered an intricate crosstalk, whereby AIRE may promote prothymosin cleavage to Tα1, and Tα1 in turn transcriptionally regulates AIRE expression. Thus, similar to other members of thymic stromal poietins, Tα1 expressed within the thymus and peripheral tissues regulates the EC/DC crosstalk required for salutary immune homeostasis.