title: Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing precursors in the cortico-medullary junction.
abstract: The thymic epithelium forms specialized niches to enable thymocyte differentiation. While the common epithelial progenitor of medullary and cortical thymic epithelial cells (mTECs and cTECs) is well defined, early stages of mTEC lineage specification have remained elusive. Here, we utilized in vivo targeting of mTECs to resolve their differentiation pathways and to determine whether mTEC progenitors participate in thymocyte education. We found that mTECs descend from a lineage committed, podoplanin (PDPN)-expressing progenitor located at the cortico-medullary junction. PDPN(+) junctional TECs (jTECs) represent a distinct TEC population that builds the thymic medulla, but only partially supports negative selection and thymocyte differentiation. Moreover, conditional gene targeting revealed that abrogation of alternative NF-κB pathway signaling in the jTEC stage completely blocked mTEC development. Taken together, this study identifies jTECs as lineage-committed mTEC progenitors and shows that NF-κB-dependent progression of jTECs to mTECs is critical to secure central tolerance.
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Onder
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Nindl
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Elke
authors.initials: E
authors.lastname: Scandella
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chai
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Cheng
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Caviezel-Firner
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Novkovic
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Bomze
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Maier
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Mair
authors.affiliation: Institute of Laboratory Animal Sciences, University of Zurich, Zurich, Switzerland.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ledermann
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.affiliation: Institute of Molecular Medicine, University of Mainz, Mainz, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.|Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; C490441:Pdpn protein, mouse; D000098853:Podoplanin
keywords: Cortico-medullary junction; Nuclear factor kappa B(NF-κB); Podoplanin; Progenitor/precursor; T-cell selection; Thymus; mTec