Thymic Epithelial Cells Contribute to Thymopoiesis and T Cell Development

Abstract

The thymus is the primary lymphoid organ responsible for the generation and maturation of T cells. Thymic epithelial cells (TECs) account for the majority of thymic stromal components. They are further divided into cortical and medullary TECs based on their localization within the thymus and are involved in positive and negative selection, respectively. Establishment of self-tolerance in the thymus depends on promiscuous gene expression (pGE) of tissue-restricted antigens (TRAs) by TECs. Such pGE is co-controlled by the autoimmune regulator (Aire) and forebrain embryonic zinc fingerlike protein 2 (Fezf2). Over the past two decades, research has found that TECs contribute greatly to thymopoiesis and T cell development. In turn, signals from T cells regulate the differentiation and maturation of TECs. Several signaling pathways essential for the development and maturation of TECs have been discovered. New technology and animal models have provided important observations on TEC differentiation, development, and thymopoiesis. In this review, we will discuss recent advances in classification, development, and maintenance of TECs and mechanisms that control TEC functions during thymic involution and central tolerance.

Combined transient ablation and single-cell RNA-sequencing reveals the development of medullary thymic epithelial cells

“…The remaining three clusters, dubbed ‘TAC-TEC’, ‘ Aire- positive’, and ‘Late- Aire ’ based on subsequent analysis, included cells that expressed Aire and Fezf2 and resembled populations previously described as mTEC3 ( Kernfeld et al, 2018 ), mTEC-II and mTEC-III ( Bornstein et al, 2018 ), and mTEhi and mTEClo ( Miragaia et al, 2018 ; Figure 1c and d , Figure 1—figure supplement 1c ). As further validation of our clustering, we restricted the list of differentially expressed genes to only those annotated as transcription factors and chromatin modifiers because these functional categories are known to be important in TEC biology ( Wang et al, 2019 ; Figure 1—figure supplement 1d ). We anticipated that differential expression analysis between clusters would be enriched for specific genes previously associated with mTEC function.…”

The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

“…Positively selected SP migrate from the thymic cortex into the medulla to undergo negative selection. The thymic medulla is populated by medullary TEC (mTEC), DC, and B cells which present peripheral tissue-specific antigens (TSA) ( 101 – 103 ). mTEC express the transcription factors autoimmune regulator (AIRE) and forebrain expressed zinc finger 2 (Fezf2), which drive expression of a spectrum of TSA, including β cell-expressed proteins such as insulin ( 104 – 109 ).…”

Intrathymic Selection and Defects in the Thymic Epithelial Cell Development

“…The medulla displays an important array of mTEC subsets whose functions in the thymocyte education has been extensively studied [ 11 , 48 ]. Currently, it is assumed the existence of immature mTECs, mature mTECs implicated in negative selection and the production of Treg cells, and a post mature stage whose functional significance is more controversial.…”

“…Positively selected SP thymocytes up-regulate the expression of CCR7 and migrate into the medulla through the cortico-medullary junction to interact with medullary (m) TECs that express ligands of CCR7 (i.e., CCL19, CCL21) [ 7 ]. mTECs have the capacity to present peptides derived from tissue proteins (TSA, tissue specific antigens) expressed outside the thymus with the concourse of, at least, two different transcription factors: Autoimmune regulator (Aire) [ 5 , 8 , 9 , 10 , 11 ] and Forebrain embryonic Zn-finger-like (Fefz2) [ 12 ]. These mTEC–thymocyte interactions are essential for the induction of thymic selection, as thymocytes whose TCRαβ recognize with high-affinity TSA are eliminated by apoptosis (negative selection) [ 5 , 10 ] or differentiate to Treg cells [ 3 ].…”