T cells originate in the bone marrow (BM) but migrate to the thymus to undergo development and maturation [1–3]. This maturation is central to the development of a functional immune system and relies initially on the selection of high-quality T cell receptor (TCR) clones. TCR generation in the thymus is achieved through random somatic gene rearrangements , giving rise to T cells with an array of receptors capable of recognizing an immense repertoire of antigens. In the classic model of tolerance, TCRs in the thymus cortex are presented initially in the context of major histocompatibility (MHC)-restricted self-antigens, and only those with sufficient affinity/avidity survive. In contrast, TCRs with very low or no affinity/avidity die by neglect . T cells pass subsequently to the thymic medulla, where they again encounter MHC-restricted self-antigens. Here, receptors that show high affinity/avidity for self-antigens are deleted in a process called negative selection. In principle, this process of positive and negative selection gives rise to a T cell repertoire tolerant to self-antigens, and which is able to recognize non-self-antigens in the context of self-MHC.
The issue of how T cells in the thymus can be exposed to self-antigens, which should be expressed only in a tissue-restricted fashion outside the thymus, was previously unclear. It has become apparent that cells in the thymus can express a selected set of proteins which are otherwise limited to specific tissues within the body. Expression of these tissue-restricted antigens (TRAs) within the thymus has now been demonstrated for a number of antigens in both mice and humans, and at both RNA and protein levels [6–11]. While TRAs are expressed primarily by medullary thymic epithelial cells (mTECs) within the thymus [6–8,10,12–15], cells of haematopoietic origin such as dendritic cells (DCs) also appear capable of expressing these self-antigens [15–20]. Indeed, some TRAs may be expressed by both cell types [6,7,15,16].
Prevention of autoimmune disease is therefore dependent on the correct display of TRAs in the thymus. Indeed, low levels of thymic insulin expression is associated with progression to Type I diabetes, whereas high levels appear to be protective, possibly reflecting more efficient deletion of insulin-reactive T cells [9,11]. The control of thymic TRA expression is clearly an area of considerable interest because it may hold the key to understanding the pathogenesis of autoimmune diseases.
More recently it has become clear that TRAs are also expressed in peripheral lymphoid tissues [21–26] and it is likely that here also they contribute to the process of immune tolerance.
A transcription factor encoded by the autoimmune regulatory gene (AIRE – human, Aire – murine) appears to be involved in thymic TRA expression and this has received enormous attention over the past 10 years . Given the peripheral expression of TRAs, it is possible that Aire also plays a role in peripheral TRA expression.
The aim of this review is to examine the evidence for the expression and function of Aire in peripheral, non-thymic tissue.