Medullary Thymic Epithelial Stem Cells Maintain a Functional Thymus to Ensure Lifelong Central T Cell Tolerance

•mTECSCs generated during thymic ontogeny assure lifelong mTEC generation•SSEA-1+Cld3,4hi embryonic progenitors contain self-renewing clonogenic TECs•Adult SSEA-1+Cld3,4hi TECs retain mTEC reconstitution potential•Thymopoiesis causes postnatal decline of mTECSC activity

SummaryMedullary 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 Cld3,4hi TECs contained self-renewable clonogenic TECs, capable of preferentially generating mature mTECs in vivo. Adult SSEA-1+Cld3,4hi 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.

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