The thymus produces a large number of T cells with properly selected 34repertoires. Medullary thymic epithelial cells (mTECs) are essential for T cell tolerance induction in the thymus. mTECs ectopically express and pres-ent thousands of tissue-specific antigens (TSAs) to developing T cells in the thymus, and T cells that recognize TSAs with high affinity undergo apoptosis (negative selection) or are converted into regulatory T cells, which are critical for suppressing the onset of autoimmune diseases.In various regenerative tissues, transit-amplifying cells are an intermedi-ate population linking stem cells and mature cells. Previous studies suggest that mTECs undergo homeostatic turnover, with a duration of approximately 14 days, implying the presence of transit amplifying cells in the adult thymus. However, the presence of transit-amplifying cells among adult mTECs remains unclear. We performed single cell RNA-seq analysis of TECs to elucidate het-erogeneity and differentiation dynamics of mTECs in the adult thymus and identified a candidate cluster for transit amplifying mTECs. We further con-firmed the existence of transit amplifying mTECs by cell labeling and fate map-ping analyses.In the thymus, immature thymocytes undergo positive selection that is cru-cial for generation of a self-MHC-restricted TCR repertoire. However, detailed mechanisms underlying this thymic positive selection remain to be determined. Deadenylation of mRNA poly(A) tails is the rate-limiting step in mRNA trans-lation, but its role in thymic positive selection has not been determined. We have reported that the deadenylase CCR4-NOT complex controls positive se-lection of thymocytes by suppressing aberrant up-regulation of pro-apoptotic molecules during positive selection.As disturbance of adult thymic homeostasis provokes immunodeficiency, autoimmunity, thymoma, and other diseases, these studies will aid the develop-ment of novel therapeutic strategies against such thymus-related diseases.Figure: Single cell RNA-seq analysis reveals heterogeneity and differentiation dynamics of thymic epithelial cells in the adult thymusRNA velocity analysis of single RNA-seq data reveals the differentiation trajectory of medullary thymic epithelial cells in the adult thymus.Recent Major PublicationsIto-Kureha T, Miyao T, Nishijima S, Suzuki T, Koizumi SI, Villar-Briones A, Takahashi A, Akiyama N, Morita M, Naguro I, Ishikawa H, Ichijo H, Akiyama T*, Yamamoto T*. The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression. Nat Commun 11, 6169 (2020)Akiyama T*, Horie K, Hinoi E, Hiraiwa M, Kato A, Maeka-wa Y, Takahashi A, Furukawa S. How does spaceflight affect the acquired immune system? NPJ Microgravity 6, 14 (2020)Nakamura T, Hashikawa C, Okabe K, Yokote Y, Chirifu M, Toma-Fukai S, Nakamura N, Matsuo M, Kamikariya M, Okamoto Y, Gohda J, Akiyama T, Semba K, Ikemizu S, Otsuka M, Inoue JI, Yamagata Y*. Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity. Sci Rep 10, 5152 (2020)Laboratory for Immune HomeostasisTeam Leader: Taishin Akiyama
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