Aire and T cell development

Abstract

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified.

Figure 1. Current model of Aire function in medullary thymic epithelial cells (mTECs)

Aire is expressed in the nucleus of mTECs where its primary function is to upregulate the expression of tissue specific antigens (TSAs). Aire functions in a large molecular weight complex composed of a large number of binding partners (gray ovals). These antigens are processed and presented by mTECs directly to both CD4+ and CD8+ T cells, or acquired by dendritic cells (DCs) for processing and presentation to both CD4+ and CD8+ T cells. Recognition of these antigens with high affinity results in deletion of self-reactive T cells to prevent release of these cells into the periphery to provoke autoimmunity. Additional functions for Aire have also been proposed, including expression of chemokines, antigen (Ag) presentation and processing factors, apoptotic factors, and factors important in mTEC ontogeny.