Abstract
It is well known that the most important feature of adaptive immunity is the specificity that provides highly precise recognition of the self, altered-self, and non-self. Due to the high specificity of antigen recognition, the adaptive immune system participates in the maintenance of genetic homeostasis, supports multicellularity, and protects an organism from different pathogens at a qualitatively different level than innate immunity. This seemingly simple property is based on millions of years of evolution that led to the formation of diversification mechanisms of antigen-recognizing receptors and later to the emergence of a system of presentation of the self and non-self antigens. The latter could have a crucial significance because the presentation of nearly complete diversity of auto-antigens in the thymus allows for the “calibration” of the forming repertoires of T-cells for the recognition of self, altered-self, and non-self antigens that are presented on the periphery. The central role in this process belongs to promiscuous gene expression by the thymic epithelial cells that express nearly the whole spectrum of proteins encoded in the genome, meanwhile maintaining their cellular identity. This complex mechanism requires strict control that is executed by several transcription factors. One of the most important of them is AIRE. This noncanonical transcription factor not only regulates the processes of differentiation and expression of peripheral tissue-specific antigens in the thymic medullar epithelial cells but also controls intercellular interactions in the thymus. Besides, it participates in an increase in the diversity and transfer of presented antigens and thus influences the formation of repertoires of maturing thymocytes. Due to these complex effects, AIRE is also called a transcriptional regulator. In this review, we briefly described the history of AIRE discovery, its structure, functions, and role in the formation of antigen-recognizing receptor repertoires, along with other transcription factors. We focused on the phylogenetic prerequisites for the development of modern adaptive immunity and emphasized the importance of the antigen presentation system.
Highlights
It is known that there are self-antigens with specific tissue-limited expression called tissue-specific antigens (TSAs) [1,2]
It is suggested that at a certain stage, weak Notch-signaling intensifies FoxN1-signalling in cortical thymic epithelial precursors cells (cTEPCs), which leads to the maturation of functional cortical thymic epithelial cells (cTECs) or Nurse-cells [71,73,74]
A lack of mechanisms of antigen presentation in jawless vertebrates imposed limitations on the capability of the immune system to recognize self-altered or damaged self-antigens that can appear as a result of mutations or infections
Summary
It is known that there are self-antigens with specific tissue-limited expression called tissue-specific antigens (TSAs) [1,2]. Genetic studies allowed the researchers to identify a new gene located in this locus, determine its nucleotide sequence, and suggest its involvement in the regulation of the transcription because of two zinc fingers in its structure [12,13,14] Later, it was called autoimmune regulator (Aire) because of a direct association between mutations in this gene and APECED syndrome [15,16]. Only in 2001 did the analysis of a major set of TSA genes in various populations of the thymic cells show that all were expressed primarily in the mTECs population (medullary thymic epithelial cells), and that the level of their expression was closely associated with the expression of AIRE [17] It was suggested on the role of the Aire gene in the presentation of self-antigens in the thymus and possible maintenance of self-tolerance
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