Aire is predominantly expressed in the thymus, suggesting an important role in immune regulation (25
). Within the thymus, Aire is expressed in a subset of stromal cells known as medullary thymic epithelial cells (mTECs). mTECs have the unusual property of displaying a variety of peripheral self-antigens, including known autoimmune targets such as insulin and thyroglobulin (26
) (). This expression of peripheral self-antigens had been proposed to be important in allowing self-reactive T cells that recognize these self-antigens to be deleted. In this process, termed negative selection, T cells that recognize self-antigen in the thymus would be prevented from being released into the body and thus prevented from causing autoimmune disease. It was, therefore, hypothesized that Aire might be playing an important role in driving the expression of these peripheral self-antigens in mTECs.
Figure 1 Negative selection of T cells in normal and Aire-deficient thymi. A, Thymic negative selection in the normal state. Progenitor T cells undergo T-cell receptor rearrangement in the thymus, which generates by chance a subset of self-reactive cells (black (more ...)
Indeed, Aire-deficient mice, developed as a model of human APS type I, have decreased expression of a number of organ-specific self antigens in mTECs (29
). Additionally, these mice also have defective negative selection of T cells in the thymus (30
). Like humans with homozygous null mutations in Aire, these mice develop tissue-specific autoimmune disease in multiple organs. The autoimmune disease is characterized both by a lymphocytic infiltrate in the targeted organ and the presence of serum autoantibodies reactive against the targeted organ.
These data are consistent with a model in which self-reactive T cells in the thymus are normally removed from the T-cell repertoire (). Aire plays an important role in the normal thymus in that it increases the expression of thymic self-antigens, and the presentation of these antigens drive the negative selection of self-reactive T cells (32
). Without Aire, a number of self-antigens are no longer transcribed in mTECs and self-reactive T cells can escape into the periphery to cause autoimmunity (). These self-antigens have been shown to be enriched for organ-specific self-antigens (29
), perhaps explaining why APS type I patients develop a number of organ-specific autoimmune diseases.
More recently, Aire has been proposed to play an additional role in guarding against autoimmunity in extrathymic immune sites (33
). Studies in a mouse that expresses a fluorescent tag in Aire-expressing cells showed that a unique subset of cells in the lymph node and spleen also express Aire (33
). Like mTECs, these cells, termed extrathymic Aire-expressing cells (eTACs), are able to delete autoreactive T cells in a transgenic system. Furthermore, these eTACs, like mTECs, express a number of organ-specific antigens in an Aire-dependent manner. The antigens expressed in eTACs were nonoverlapping with mTECs, suggesting that these two cell types may have nonredundant functions and protect against a different repertoire of self-reactive T cells.
The mechanism by which Aire functions to up-regulate thymic self-antigen expression in mTECs remains to be fully elucidated. The Aire protein contains a number of domains that suggest that it plays a role in transcription (32
). In particular, Aire contains two PHD (plant homeodomain) domains, which have recently been shown in a number of proteins to bind trimethylated histone H3 (H3K4me3) (35
). Unlike the PHD domains in these other proteins, PHD1 in Aire seems to bind histone H3 in the unmethylated state (37
). Despite this difference, this finding nevertheless suggests a link between Aire and chromatin pattern recognition. Additionally, Aire has been shown to bind to three proteins with described roles in transcription: 1) positive transcription elongation factor b (pTEFb) (39
), 2) DNA-dependent protein kinase (DNA-PK) (40
), and 3) cAMP response element-binding protein (CBP) (41
). How these proteins interact together in Aire-mediated transcription remains to be determined.