The Role of Aire, microRNAs and Cell-Cell Interactions on Thymic Architecture and Induction of Tolerance.

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Background

Developing thymocytes interact sequentially and in a three-dimensional architecture with two distinct structures within the thymus, the cortex where the double negative (DN) and double positive (DP) thymocytes interact with cortical thymic epithelial cells (cTECs) ensuring MHC-mediated self-peptide presentation to DP thymocytes expressing α/β T cell receptor (α/β TCR) featuring intermediate affinity/avidity. The positive selection is a result of this interaction, which leads the DP thymocytes differentiate into mature single-positive (SP) thymocytes. The DP thymocytes that fail to positive selection are eliminated through death by neglect. Thereafter, the surviving SP and DP thymocytes migrate into the thymic medulla where they interact with medullary thymic epithelial cells (mTECs). These cells are very peculiar, because they express ectopically an enormous set of peripheral tissue antigens (PTAs). This means it is possible find insulin, a PTA that represents pancreatic beta cells and a myriad of other autoantigens in the thymus. The immunological significance of this property, which was termed promiscuous gene expression (PGE) is associated with presentation of PTAs by mTECs to SP and DP thymocytes. Those clones of thymocytes that express α/β TCR with high affinity for PTAs are eliminated by apoptosis, in a process termed negative selection or clonal deletion, essential for tolerance induction. This massively prevents passage of autoreactive T cell clones to the periphery, which could provokes aggressive autoimmunity. Therefore, the migration of thymocytes within the thymus is a property that enables the physical association of these cells with the different thymic microenvironments. Immunologists are interested in the elucidation of which chemotactic factors and/or adhesion molecules are involved in this process. Another very important factor is the autoimmune regulator (Aire) gene that controls the expression of large set (but not all) PTAs in mTECs. Lack of function of this gene, often caused by mutations, is the basis of APECED an autoimmune disease that is characterized by hypoparathyroidism, candidiasis (yeast infection) and adrenal insufficiency. The mechanism of the Aire gene as a transcriptional regulator of Aire-dependent PTAs and also the effect of point mutations found in the Aire gene sequence on clinical phenotype (APECED or other autoimmune diseases) are receiving attention in recent years. In addition, researchers observed that besides PTAs, Aire controls the expression of microRNAs (miRNAs) in mTECs. In turn, miRNAs are important in the organization of thymic architecture and play a role as posttranscriptional controllers of PTAs. In this Research Topic we intent to welcome reviews or original research papers covering all aspects of T cell development within the human or murine thymus, cTEC-/mTEC-thymocyte interaction including the role of adhesion molecules during positive and negative selection, migration of thymocytes across the thymic microenvironments, Aire gene mutations and autoimmune diseases, the molecular mechanism of Aire and finally the role of miRNAs in the architecture of the thymus and as posttranscriptional controllers of PTAs, which could influence the induction of tolerance.

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