Induction of T cell self-tolerance in the thymus is controlled by medullary 35thymic epithelial cells (mTECs), which express thousands of Tissue-specific Antigens (TSAs), regulated by the AIRE transcription factor. TSAs are directly or indirectly presented to T cells in the thymus. When recognizing TSAs with high affinity, developing T cells undergo apoptosis or are converted into regula-tory T cells in the thymus.mTEC turnover is homeostatic in the adult thymus with a duration of ap-proximately 2 weeks. However, cellular and molecular mechanisms underlying the maintenance of adult mTECs remain elusive. We performed an integrative analysis of single-cell assays for transposase accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) of adult murine TECs. Data analysis suggested that AIRE-expressing (AIRE+) mTECs are separated into two subsets with distinct gene expression profiles and chromatin accessibility. One subset expresses a high level of proliferation markers and may be equivalent to transit-amplifying cells (TACs). In general, TACs are defined as a proliferative cell population linking stem cells and differentiated cells. In addition, TACs are short-lived and undergo differentiation after a few cell divisions. In order to verify the presence of TACs of mTECs (TA-TECs) in adult thymus, we isolated the proliferating mTEC subset expressing AIRE as a TA-TEC candidate by uti-lizing the Fucci technology, which allows visualization of cell cycle progression in living cells. This proliferating Aire+ mTEC subpopulation showed very low expression of TSAs regulated by AIRE, in contrast to quiescent AIRE+ mTECs. Moreover, studies using in vivo BrdU pulse-labeling and in vitro reaggregated thymic organ culture suggested that the proliferating AIRE+ mTECs are short-lived and that they differentiate into quiescent AIRE+ mTECs and later differ-entiation stages of mTECs. Accordingly, we conclude that these proliferating AIRE+ mTECs are TACs for mTECs expressing TSAs. Consequently, we pro-pose a cellular mechanism for mTEC differentiation in the adult thymus.As disturbance of TECs provokes immunodeficiency and autoimmunity, this study will aid the development of novel therapeutic strategies against such TEC-associated diseases.Figure: A proposed mechanism for the differen-tiation of mTECs in adult thymusTransit amplifying AIRE+ mTECs (TA-TEC) differentiate into AIRE+ mTEC and subsequently other mature types of mTEC (Post-AIRE mTEC, Tuft-like mTEC and Gp2+ mTEC). The stem/progenitor cells of adult mTECs remain elusive.Recent Major PublicationsAkiyama T, Yamamoto T. Regulation of Early Lymphocyte Development via mRNA Decay Catalyzed by the CCR4-NOT Complex. Front Immunol 12, 715675 (2021)Akiyama T, Suzuki T, Yamamoto T. RNA decay machinery safeguards immune cell development and immunologi-cal responses. Trends Immunol 42, 447 (2021)Ishikawa T, Akiyama N, Akiyama T. In Pursuit of Adult Progenitors of Thymic Epithelial Cells. Front Immunol 12, 621824 (2021)Invited presentationsAkiyama T. “Single Cell RNA-seq Analysis of Human Thy-mic Epithelial Neoplasms” RIKEN IMS Joint Human and Mouse Cell Atlas Meeting (Yokohama, Japan/Online) October 2021Akiyama T. “Mechanisms of thymic T cell selection and onset of autoimmune diseases” Rheumatology Confer-ence 2021 (Tokyo, Japan/Online) June 2021Laboratory for Immune HomeostasisTeam Leader: Taishin Akiyama
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