Update on Aire and thymic negative selection

Abstract

SummaryTwenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological -i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases.

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

“…A complex interaction between multiple genes on chromosome 21 may be responsible for autoimmunity in DS. The autoimmune regulator gene, AIRE, which is in the minimal region for DS on chromosome 21, regulates the ectopic expression of tissue-restricted antigens in the thymus to expose developing T cells to self-peptides; those that are strongly reactive are removed or reprogrammed (26). Mutations in AIRE cause autoimmune polyendocrine syndrome type 1, which commonly includes endocrine autoimmunity (27).…”

The Autoimmune Regulator (Aire) transactivates HLA‐G gene expression in thymic epithelial cells

“…1,2 The major regulator of negative selection is the AIRE gene (Autoimmune Regulator) that encodes a transcription factor expressed particularly, but not exclusively, on the CD80 hi MHC-II hi medullary thymic epithelial cells (mTECs) and intrathymic dendritic cells (DCs). [3][4][5] Aire is located within the nuclear speckles associated with a multimeric transcriptional complex composed by proteins related to nuclear transport, chromatin modification and transcription initiation, such as DNA-dependent protein kinase (DNA-PK); topoisomerase 2a (TOP2a) and topoisomerase 1 (TOP1) that co-localizes with super-enhancers to promote the association with Aire-containing I M M U N O L O G Y O R I G I N A L A R T I C L E complexes; 6 RNA polymerase II (RNAPII); Ku80 and Ku70. [3][4][5] Aire is located within the nuclear speckles associated with a multimeric transcriptional complex composed by proteins related to nuclear transport, chromatin modification and transcription initiation, such as DNA-dependent protein kinase (DNA-PK); topoisomerase 2a (TOP2a) and topoisomerase 1 (TOP1) that co-localizes with super-enhancers to promote the association with Aire-containing I M M U N O L O G Y O R I G I N A L A R T I C L E complexes; 6 RNA polymerase II (RNAPII); Ku80 and Ku70.…”

“…1,2 The major regulator of negative selection is the AIRE gene (Autoimmune Regulator) that encodes a transcription factor expressed particularly, but not exclusively, on the CD80 hi MHC-II hi medullary thymic epithelial cells (mTECs) and intrathymic dendritic cells (DCs). 3,4 Aire coordinates the medullary expression of hundreds of tissue-related antigens (TRAs) from peripheral tissues, by the phenomenon known as promiscuous gene expression (PGE), [3][4][5] ensuring the exposure of the majority of antigens from periphery within the medullary compartment during thymic selection. [3][4][5] Aire is located within the nuclear speckles associated with a multimeric transcriptional complex composed by proteins related to nuclear transport, chromatin modification and transcription initiation, such as DNA-dependent protein kinase (DNA-PK); topoisomerase 2a (TOP2a) and topoisomerase 1 (TOP1) that co-localizes with super-enhancers to promote the association with Aire-containing 6 RNA polymerase II (RNAPII); Ku80 and Ku70.…”

“…3,4 Aire coordinates the medullary expression of hundreds of tissue-related antigens (TRAs) from peripheral tissues, by the phenomenon known as promiscuous gene expression (PGE), [3][4][5] ensuring the exposure of the majority of antigens from periphery within the medullary compartment during thymic selection. [3][4][5] Aire is located within the nuclear speckles associated with a multimeric transcriptional complex composed by proteins related to nuclear transport, chromatin modification and transcription initiation, such as DNA-dependent protein kinase (DNA-PK); topoisomerase 2a (TOP2a) and topoisomerase 1 (TOP1) that co-localizes with super-enhancers to promote the association with Aire-containing 6 RNA polymerase II (RNAPII); Ku80 and Ku70. 7 Additionally, Aire co-localizes with CREB-binding protein, positive transcription elongation factor (P-TEFb) and ribonucleoproteins.…”

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

“…Histocompatibility antigens are prime targets for T cells because they stimulate a high avidity T-cell repertoire. Histocompatibility antigens are not expressed in donor thymus, therefore T cells recognizing histocompatibility antigens with high functional avidity do not undergo negative selection prior their adoptive transfer in patients (18,19). Moreover, the high frequency of GVHD occurrence in recipient of multiparous female donors hints at the possibility of sensitization to host recipient antigens and the mobilization of a memory T-cell repertoire against these antigens (20).…”