Thymic epithelial cell

The final anatomical location of the thymic gland is reached at 6 weeks in the fetus. TECs originate from non-hematopoietic cells that are characterized by negative expression of CD45 and positive expression of EpCAM. Then TECs are divided into two phenotypically and functionally different groups that have distinct location, cytokeratin expression, surface markers, maturation factors, proteases and function in a T cell selection. Cortical thymic epithelial cells (cTECs) are presented in the outer thymic cortex region, in comparison with medullary thymic epithelial cells (mTECs) located in the inner thymic medulla. Both cTEC and mTEC participate in imposing central and peripheral tolerance. cTECs play a key role in the positive selection and mTECs eliminate auto-reactive thymocytes during the negative selection.[2] Both of these types of cells can be defined and reciprocally distinguished by their expression of cytokines, chemokines, costimulatory molecules, and transcription factors, which have an effect on thymocyte development.[4] TECs, situated in the corticomedullary junction, express two types of cytokeratin: K5 and K8. From these immature progenitors K5+K8+ TECs are derived mTECs with typical expression of K5, K14 and also cTECs, characterized by K8, K18 expression.[2]

The first steps of TEC development are regulated by the transcription factors (Hoxa3, Pax1/9, Eya1, Six1/4, Tbx1), most of which are in postnatal cTEC and immature TECs. The most important transcription factor for all stages of TEC development in embryonic and postnatal thymus is a Foxn1. Foxn1 controls the whole process by the activation of its target genes with binding to specific DNA sequence via its forkhead box domain. There are highlighted over 400 Foxn1 targeted genes, included critical loci for TEC differentiation and function. TEC development require activity of other molecules and transcriptional regulators, such as protein 63 (p63) that is involved in homeostasis of various epithelial lineages, chromobox homolog 4 (Cbx4) which regulates cell proliferation and differentiation, fibroblast growth factors Fgf7 and Fgf10 that initiate TEC expansion, TNFT, CD40, lymfotoxin β receptor (LTβR) and Hedgehog signaling pathway, which could reduce TEC cells in fetal and postnatal thymus.[1][6] These typical molecules for TEC progenitors development are mostly similar and shared with cTEC. The early stages of cTEC also require high expression of Pax 1/9,Six1/4,Hixa3 but they could be established in the absence of NFκB. In contrast, mTEC development is dependent on the presence of Relb, NFκB signals and the TNFR superfamily but it could be performed in the absence of Foxn1.[1][6]

TECs, as a component of the thymus, play a key role in thymocyte development and self-tolerance, so their dysfunction causes many autoimmune diseases, tumors of immunodeficiencies. Most frequently are occurred epithelial tumors established from TEC and thymocytes - thymomas and thymic carcinoma. Maturation abnormalities of TECs induce chronic inflammatory diseases and decreased count of mTEC and cTEC leads to chronic inflammatory bowel disease (IBD). Autoimmune disease development is result of a break down of the self-tolerance by Aire-mediated TRAs' expression on mTEC or the negative regulatory system formed by CD4+CD25+Foxp3 nTreg cells. Aire mediates negative selection of auto-reactive T-cells and organ-specific antigens' expression on mTECs. The outcome of a single gene mutation in the autoimmune regulator Aire is systematic disease APECED (APS-1), which is manifested by mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. There are many autoimmune diseases, caused by failure of self-tolerance by TRAs on mTEC, for example autoimmune thyroiditis, rheumatoid arthritis or multiple sclerosis. Type 1 diabetes is a result of the absence of self-tolerance, which is characterized by a decreased expression of Insulin 1 and Insulin 2 (TRAs) on mTEC. mTEC and cTEC damage is observed during Graves' disease, Myasthenia gravis or HIV.[2]

List of distinct cell types in the adult human body