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. 2022 Jan 7;11(2):194. doi: 10.3390/cells11020194

Figure 4.

Figure 4

Recent technological approaches made it possible to identify a high level of TECs heterogeneity and reveal the existence of various cTEC and mTEC subpopulations with distinct molecular and functional characteristics. This figure shows a simplified scheme of cTEC/mTEC differentiation at the embryonic period. Thymic epithelial progenitor cells (TEPCs) are supposed to give rise to two main lineages of thymic epithelial cells—cortical and medullary. TEPCs colonize the thymus in early embryogenesis, have spontaneous Notch expression, and are capable of self-renewal because of a high level of Notch-signaling due to the lateral induction mechanism. TEPCs are assumed to commit to the cTEC lineage by default without a Notch signal, becoming renewable cortical progenitor cells (cTEPCs). Low Notch-signal at this stage can upregulate FoxN1 and induce differentiation of cTEPCs to cTECs or Nurse Cells. TEPCs that experience a low level of Notch-signaling commit to the mTEC lineage and form renewable medullary progenitor cells. Subsequent differentiation of mTEPCs occurs during “thymic crosstalk” between epitheliocytes and maturating lymphocytes and relies on FoxN1-signaling, TNFRSF, and RANK-NF-κB pathways. That is accompanied by upregulation of UEA, MHC-II, and B7 cell surface expression. Then Histone deacetylase 3 downregulates Notch-signaling to result in differentiation of functional AIRE+mTECshi, which soon undergo terminal differentiation or apoptosis and form post-AIRE structures as post-AIRE cells, Tuft-cells, or Hassall’s corpuscles. These post-AIRE structures have an essential role in the TSA presentation to maturating lymphocytes, particularly TSA transfer to dendritic cells is critical for optimal presentation of some self-antigens. In addition, recent studies have shown that in the thymus, at least in mice, there are Pdpn+ junctional thymic epithelial cells (jTECs), which are localized at the cortico-medullary junction. These cells are renewable and give rise to mTEClo and AIRE+mTEChi subsets in adulthood.