title: Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK(+) medullary epithelial progenitors.
abstract: Thymic epithelial cells (TECs) provide essential signals for αβT-cell development, and medullary TECs (mTECs) control T-cell tolerance through both negative selection and Foxp3(+) regulatory T (Treg) cell development. Although heterogeneity within the mTEC compartment is well studied, the molecular regulators of specific stages of mTEC development are still poorly understood. Given the importance of the RANK-RANKL axis in thymus medulla formation, we have used RANK Venus reporter mice to analyze the ontogeny of RANK(+) TECs during development and correlated RANK expression with mTEC stem cells defined by SSEA-1. In addition, we have investigated how requirements for the key regulators Foxn1 and Relb map to specific stages of mTEC development. Here, we show SSEA-1(+) mTEC stem cells emerge prior to RANK expression and are present in both nude and Relb(-/-) mice, providing direct evidence that mTEC lineage specification occurs independently of Foxn1 and Relb. In contrast, we show that Relb is necessary for the effective production of downstream RANK(+) mTEC progenitors. Collectively, our work defines stage-specific requirements for critical TEC regulators during medulla development, including the timing of Relb dependency, and provides new information on mechanisms controlling mTEC specification.
authors.affiliation: MRC Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
authors.forename: Song
authors.initials: S
authors.lastname: Baik
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 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, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hamazaki
authors.affiliation: MRC Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
authors.forename: William E
authors.initials: WE
authors.lastname: Jenkinson
authors.affiliation: MRC Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016256:Lewis X Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013234:Stem Cells / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D016256:Lewis X Antigen; D053246:Receptor Activator of Nuclear Factor-kappa B; D016693:Receptors, Antigen, T-Cell, alpha-beta; C497594:Relb protein, mouse; C505687:Tnfrsf11a protein, mouse; C090140:Whn protein; D051841:Transcription Factor RelB
keywords: Foxn1; Stem cell; TNF receptor superfamily; Thymic epithelium; Thymic microenvironments; Thymus