The role of Aire in clonal selection

Abstract

In his clonal selection theory, Frank Macfarlane Burnet predicted that autoreactive lymphocytes are deleted to prevent autoimmunity. This and other principles of lymphocyte behavior outlined by Burnet guided many studies that lead to our current understanding of thymic selection. Thus, when the genetic mutation responsible for autoimmune polyglandular syndrome type 1 was mapped to the autoimmune regulator (AIRE) gene, and Aire was found to be highly expressed in thymic epithelium, studying the role of Aire in negative selection made sense in the context of modern models of thymic selection. We now know Aire is a transcription factor required for the expression of many tissue-specific antigens (TSAs) in the thymus. In the absence of functional Aire, human patients and mice develop multi-organ autoimmune disease because of a defect in thymic negative selection. In addition to its role in the thymus, recent work in our lab suggests that extrathymic Aire-expressing cells have an important role in the clonal deletion of autoreactive CD8+ T cells. In this review, we summarize the latest studies on thymic and peripheral Aire-expressing cells, as well as other TSA-expressing stromal cell populations in peripheral lymphoid organs. We also discuss theoretical differences in thymic and peripheral Aire function that warrant further studies.

Figure 1. Functional domains in Aire that are common to other transcription factors

Aire contains a CARD/HSR domain, nuclear localization sequences (NLS), a SAND domain, two PHD zinc finger domains, and a PRR which are structures found in other transcription factors.

Figure 2. Model of T cell activation by APC under steady state conditions or during a viral infection

Under steady state conditions, CD8+ T cells are deleted by eTACs, FRCs, and hematopoetic DC, while CD4+ T cells proliferate and become anergic. Upon TLR3 engagement by virus-derived, double stranded RNA, FRCs may decrease self antigen presentation while hematopoetic DCs mature to activate T cells.