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.

Keywords: medullary thymic epithelial cells (mTECs); thymic epithelial cells (TECs); thymopoiesis; tissue-restricted antigens (TRAs); tolerance.

Figure 1

Updates on TEC classification. TECs can be separated into cortical and medullary TECs based on their localization in the thymus. Bipotent TEC progenitors with the ability to self-renew were identified as EpCAM⁺UEA1⁻Ly-51⁺MHCII^hiPlet1⁺ in adult thymus. cTEPs are positive for EpCAM, CD205, IL-7, and β5t. cTECs that differentiated from cTEPs are defined as EpCAM⁺Ly-51⁺CD45⁻, whereas mTECs are characterized by EpCAM⁺UEA-1⁺CD45⁻. mTEC compartments were newly reclassified into four major subsets, termed mTEC I–IV. mTEC I is EpCAM⁺CD45⁻MHCII^loITGB4⁺L1CAM^lo and usually expresses Itga6 and Sca1. The mTEC II population is considered to be mature mTECs and is defined as EpCAM⁺CD45⁻MHCII^hiLy6d⁻. mTEC II cells express Aire, Fezf2, CD40, H2-Aa, or CD74. The mTEC III population is EpCAM⁺CD45⁻MHCII^loLy6d^hiITGB4⁻L1CAM⁻ and expresses Pigr, Ly6d, Spink5, Ivl, and KRT10. Remarkably, the mTEC IV population expresses high levels of L1CAM and DCLK1 and a specific set of genes, such as Trpm5, Dclk1, and L1cam, but with low levels of MHCII.