title: Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance.
abstract: Medullary thymic epithelial cells (mTECs) are crucial for central T cell self-tolerance. Although progenitors of mTECs have been demonstrated in thymic organogenesis, the mechanism for postnatal mTEC maintenance remains elusive. We demonstrate that implantation of embryonic TECs expressing claudin-3 and claudin-4 (Cld3,4) in a medulla-defective thymic microenvironment restores medulla formation and suppresses multiorgan autoimmunity throughout life. A minor SSEA-1(+) fraction within the embryonic Cld3,4(hi) TECs contained self-renewable clonogenic TECs, capable of preferentially generating mature mTECs in vivo. Adult SSEA-1(+)Cld3,4(hi) TECs retained mTEC reconstitution potential, although the activity decreased. The clonogenicity of TECs also declined rapidly after birth in wild-type mice, whereas it persisted in Rag2(?/?) adult mice with defective thymopoiesis. The results suggest that unipotent mTEC-restricted stem cells that develop in the embryo have the capacity to functionally reconstitute the thymic medulla long-term, thus ensuring lifelong central T cell self-tolerance.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Sekai
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hamazaki@imm.med.kyoto-u.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hamazaki
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D062465:Claudin-3 / Q000096:biosynthesis; D062506:Claudin-4 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D016256:Lewis X Antigen / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D055746:Stage-Specific Embryonic Antigens / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D062465:Claudin-3; D062506:Claudin-4; D004268:DNA-Binding Proteins; D016256:Lewis X Antigen; C499308:Rag2 protein, mouse; D055746:Stage-Specific Embryonic Antigens; C052924:stage-specific embryonic antigen-3