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Emerging role of Toll-like receptors in central tolerance
Súkeníková, Lenka ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Medullary thymic epithelial cells (mTECs) provide a specific thymic microenvironment for the processes associated with T cell development. Their irreplaceable function is the expression of specific set of antigens which are expressed only in peripheral tissues, called tissue restricted antigens (TRAs). Such expression, often referred to as promiscuous, was originally described with the discovery of transcriptional regulator Aire. Aire, which has a potential to interact with many other transcription factors, also binds to DNA, and thus can alter the general pattern of cellular gene expression. T cells exhibiting a strong affinity to TRAs expressed on mTECs are removed from the thymus by negative selection or their development is deviated to regulatory T cell (Treg) lineage. Studies on mice and humans confirmed the critical role of Aire protein in the establishment of the central tolerance. Inactivating mutations in Aire gene cause deficiency in TRA expression, failure to remove and the escape of self-specific T cells from the thymus to periphery, and in turn, autoimmunity. Experimental evidence points to the key role of NF-κB signaling pathway in mTECs development. The very same pathway is regulated also by Toll-like receptors (TLRs), which recognize evolutionary conserved structures derived from...
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