Control of central and peripheral tolerance by Aire

Abstract

Summary The negative selection of self-reactive thymocytes depends on the induction of tissue-specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent, endogenous tissue-specific antigens remains to be determined.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…Autoreactive T cell progenitors expressing TCRs that bind with high affinity to self-peptide-major histocompatibility complex (MHC) complexes are deleted through a process called negative selection. The transcription factor autoimmune regulator (AIRE), which is selectively expressed by a subset of CD80-expressing medullary thymic epithelial cells (TECs), drives the expression of tissue-specific self-antigens to ensure selective removal of thymocytes bearing TCRs that recognize these antigens 12 . Thymocytes that have low affinity for self-peptide-MHC complexes are positively selected to progress to the periphery.…”

Thymosin α1: burying secrets in the thymus

“…The mTECs express a large number of genes, including tissue-specific antigens (TSAs) that are normally present only in specialized peripheral organs and are apparently not required for the direct functioning of mTECs [27]. During negative selection, these encoded TSAs are presented by mTECs or DCs as self-antigens to differentiating thymocytes, leading to the induction of tolerance either by clonal deletion, functional inactivation of self-reactive T cells or clonal deviation [28,29]. The thymic expression of many of these TSAs is dependent on the AIRE gene [30] and mutations in AIRE lead to severe, multiorgan, tissue-specific autoimmunity in both mice and humans [28].…”

MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

“…A more direct demonstration of the pathogenic potential of human CD8CT cells has been provided by the group of Peakman (67). A CD8CT-cell clone recognizing a HLA-A2-restricted PPI [15][16][17][18][19][20][21][22][23][24] epitope was capable of lysing primary human HLA-A2C islets. Interestingly, this cytotoxic activity was enhanced by increasing glucose concentrations, due to increased presentation of this epitope on the surface of b-cells.…”