Abstract
Thymic epithelial cells (TECs) orchestrate Tcell development by imposing positive and negative selection on thymocytes. Current studies on TEC biology are hampered by the absence of long-term exvivo culture platforms, while the cells driving TEC self-renewal remain to be identified. Here, we generate long-term (>2 years) expandable 3D TEC organoids from the adult mouse thymus. For further analysis, we generated single anddouble FoxN1-P2A-Clover, Aire-P2A-tdTomato, and Cldn4-P2A-tdTomato reporter lines by CRISPR knockin. Single-cell analyses of expanding clonal organoids reveal cells with bipotent stem/progenitor phenotypes. These clonal organoids can be induced to express Foxn1 and to generate functional cortical- and Aire-expressing medullary-like TECs upon RANK ligand+ retinoic acid treatment. TEC organoids support Tcell development from immature thymocytes invitro as well as invivo upon transplantation into athymic nude mice. This organoid-based platform allows invitro study of TEC biology and offers a potential strategy for exvivo Tcell development.
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