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Explore the wonderful world of Thymus: How do cTECs and mTECs shape the fate of T cells?
In our immune system, the thymus is one of the key players. As the main lymphoid organ, it guides the development and maturation of T cells. Two special cells in the thymus, cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs), play a role in this process. An irreplaceable role.
Thymic epithelial cells are highly anatomical, phenotypic, and functionally heterogeneous and are distributed in the outer layer of the thymic stroma.
The microenvironment of the thymus is established by the TEC network, which is filled with thymocytes, the precursors of blood cells at different stages of development. These epithelial cells and thymocytes are the most important components of the thymus and are crucial for the production of functionally mature T lymphocytes and self-tolerance.
TEC grouping
The structure of the thymus reaches its final anatomical position at 6 weeks of fetal development. TECs originate from non-hematopoietic cells, which are CD45-negative and EpCAM-positive on their surface. TECs are further divided into two categories, namely cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs), which have obvious differences in location, cytokeratin expression, and surface markers.
cTECs are found in the cortical region of the outer thymus, while mTECs are found in the medulla inside the thymus.
The main role of cTECs is positive selection, while mTECs are responsible for eliminating self-reactive thymocytes. Both types of cells influence the development of thymocytes by secreting cytokines, chemokines, and costimulatory molecules to form central and peripheral tolerance.
Cellular changes during maturation
Maturation of medullary thymic epithelial cells
The maturation process of mTECs involves the expression of high levels of MHC II molecules, CD80, autoimmune regulator Aire, and tissue-restricted antigens (TRAs). During this process, adult mTECs lose specific maturation factors during the terminal differentiation stage and begin to express involucrin as a marker of terminally differentiated epithelium.
Maturation of cortical thymic epithelial cells
The maturation process of cTECs is also accompanied by high expression of MHC II molecules, combined with the action of multiple proteases, such as β5t and Cathepsin L. These factors are involved in the positive selection of T cells.
Specific surface markers such as Ly51 and CD205 are crucial for the identification and characterization of cTEC.
Early cTEC also requires high expression of some transcription factors such as Pax 1/9, Six1/4, etc. These transcription factors play a core role in gene regulation for the development of TEC. In addition, mTEC development depends on the regulation of Relb and NFκB signaling pathways, while Foxn1 is no longer required.
The mechanism of positive and negative selection
Positive selection
Double-negative (DN) T cells proliferate and differentiate under the expression of markers CD44 and CD25, transforming into double-positive (DP) T lymphocytes. These cells begin to express completely recombinant TCRs and complex with the MHC of cTEC. Recognition testing of self and non-self antigens is performed on the object. Only thymocytes that properly interact with the MHC complex can survive and further differentiate into CD4+ or CD8+ single-positive (SP) T lymphocytes.
Negative selection
In the process of negative selection, mTEC plays a key role by eliminating those embryonic T cells with high affinity for self-antigens by broadly expressing the diversity of self-antigens. In this process, mTECs are not only responsible for achieving self-tolerance, but also support the development of CD4+CD25+Foxp3 T regulatory cells, which are critical for controlling immune responses.
The connection between TECs and diseases
Because of the important role of TECs in T cell development and self-tolerance, their dysfunction can lead to a variety of autoimmune diseases and immune deficiencies. For example, mutations in the autoimmune regulator Aire gene cause the systemic autoimmune disease APECED, which is characterized by thyroid abnormalities and breast hypofunction. In addition to APECED, diseases such as rheumatoid arthritis, multiple sclerosis, and type 1 diabetes are closely related to the role of TECs.
Dysfunction of thymic epithelial cells can lead to the occurrence of autoimmune diseases and tumors, with widespread and far-reaching consequences.
In summary, the microenvironment of the thymus and the functions of cTECs and mTECs not only affect the fate of T cells, but also play an important role in the health of the immune system. As we learn more about these cells, can we find new ways to restore thymus function and improve the immune system's defenses?
