![]() ![]() In addition to the classical mTEC lo (mTEC I), Aire + mTEC (mTEC II), and post-Aire mTEC (mTEC III) types, a tuft-like mTEC subset (mTEC IV) was identified ( Bornstein et al., 2018 Miller et al., 2018). showed that mTECs in the postnatal thymus are separated into four subsets, mTEC I to IV ( Bornstein et al., 2018). In TEC biology, previous scRNA-seq studies revealed the stochastic nature of TSA expression in mTECs ( Sansom et al., 2014 Meredith et al., 2015) and high heterogeneity of TECs in mice ( Bornstein et al., 2018 Miller et al., 2018 Dhalla et al., 2020 Baran-Gale et al., 2020). Single-cell RNA sequencing (scRNA-seq) technology has yielded new insights into cell diversity and differentiation in various tissues. These views are primarily based on fate mapping studies involving transfer and reaggregation of sorted cell populations with fetal thymus ( Rossi et al., 2007 Gray et al., 2007 Sekai et al., 2014) and on experiments employing genetic marking ( Metzger et al., 2013 Nishikawa et al., 2014). Moreover, a previous study suggested that mTECs might be differentiated from stage-specific embryonic antigen-1 + (SSEA-1) claudine3/4 + mTEC stem cells ( Sekai et al., 2014). Aire + mTECs are further converted into Aire-negative mTECs (post-Aire mTECs) ( Metzger et al., 2013 Michel et al., 2017 Nishikawa et al., 2014 Wang et al., 2012 White et al., 2010). CD80 lo and Aire-negative (Aire -) mTECs (mTEC lo) are thought to be immature, and they differentiate into CD80 hi Aire-expressing (Aire +) mTECs that are reportedly post-mitotic ( Gray et al., 2007). mTEC subpopulations are largely classified based on their expression of cell surface markers (mainly CD80 and MHC class II) and Aire in the adult thymus ( Abramson and Anderson, 2017). Notably, however, cellular mechanisms underlying maintenance of adult mTECs remain unclear. In addition, some previous studies have reported that mTEC turnover is homeostatic in the adult thymus, with a duration of approximately 2 weeks ( Gäbler et al., 2007 Gray et al., 2007 Gray et al., 2006). Several studies have suggested processes and underlying mechanisms of mTEC differentiation during thymic organogenesis ( Abramson and Anderson, 2017 Inglesfield et al., 2019 Rossi et al., 2007 Akiyama et al., 2016 Akiyama et al., 2005 Akiyama et al., 2008 Hikosaka et al., 2008 Mouri et al., 2011 Kajiura et al., 2004). ![]() TSAs are directly or indirectly presented to developing T cells, and T cells that recognize TSAs with high affinity undergo apoptosis or are converted into regulatory T cells, thereby suppressing the onset of autoimmune diseases ( Abramson and Anderson, 2017 Inglesfield et al., 2019). mTECs ectopically express thousands of tissue-specific antigens (TSAs), and this expression is regulated by transcription factors, AIRE and FEZF2 ( Anderson et al., 2002, Takaba et al., 2015). Medullary thymic epithelial cells (mTECs) are essential for induction of T cell self-tolerance in the thymus ( Abramson and Anderson, 2017 Inglesfield et al., 2019). These data provide evidence for the existence of transit-amplifying Aire +mTEC precursors during the Aire +mTEC differentiation process of the postnatal thymus. Proliferating Aire +CD80 hi mTECs detected using Fucci technology express a minimal number of Aire-dependent TSAs and are converted into quiescent Aire +CD80 hi mTECs expressing high levels of TSAs after a transit amplification. Integrative analysis of single-cell assays for transposase-accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules, CD80 (Aire +CD80 hi). Whereas AIRE-expressing (Aire +) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by the transcriptional regulator, AIRE. Transborder Medical Research Center, and Department of Genome Biology, Faculty of Medicine, University of Tsukuba, Japan. ![]()
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