Central tolerance to self revealed by the autoimmune regulator

Abstract

The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs has helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire has revealed multiple binding partners that assist Aire's function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance.

Keywords: APS-1; Aire; autoimmunity; mTEC.

Figure 1

The role of Aire in central tolerance. Central tolerance primarily occurs in the medullary compartment of the thymus where T cells develop (T cell progenitor to double-negative (DN) T cells to double-positive (DP) T cells and single-positive (SP) T cells). Aire is expressed in medullary thymic epithelial cells (mTECs) derived from TEC progenitors located in the corticomedullary junction of the thymus. These Aire⁺ mTECs express tissue-specific antigens (TSAs) and can hand-off these antigens to thymic dendritic cells (DCs). Post-Aire cells also express TSAs but at a lower level and are found near Hassall’s corpuscles. Expression of TSAs in the medulla affect T_reg cell generation and negative selection of T cells, which are critical for maintaining central tolerance.

Figure 2

Aire protein domains. Aire contains multiple functional domains, including caspase-recruitment domain (CARD), SAND (Sp100, AIRE-1, NucP41/75, and DEAF-1) domain, two plant homeodomain (PHD) fingers, proline rich region (PRR), and four LXXLL motifs. These domains bind different Aire-binding partners and epigenetic marks that result in Aire’s unique functions.

Figure 3

Aire-binding partners. Aire binds to multiple protein partners, enabling an influence on both transcription and chromatin remodeling.