title: Central immune tolerance depends on crosstalk between the classical and alternative NF-κB pathways in medullary thymic epithelial cells.
abstract: Medullary thymic epithelial cells (mTECs) contribute to self-tolerance by expressing and presenting peripheral tissue antigens for negative selection of autoreactive T cells and differentiation of natural regulatory T cells. The molecular control of mTEC development remains incompletely understood. We here demonstrate by TEC-specific gene manipulation in mice that the NF-κB transcription factor subunit RelB, which is activated by the alternative NF-κB pathway, regulates development of mature mTECs in a dose-dependent manner. Mice with conditional deletion of Relb lacked mature mTECs and developed spontaneous autoimmunity. In addition, the NF-κB subunits RelA and c-Rel, which are both activated by classical NF-κB signaling, were jointly required for mTEC differentiation by directly regulating the transcription of Relb. Our data reveal a crosstalk mechanism between classical and alternative NF-κB pathways that tightly controls the development of mature mTECs to ensure self-tolerance.
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany. Electronic address: marc.riemann@leibniz-fli.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Riemann
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Andreas
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Fedoseeva
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Meier
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Debra
authors.initials: D
authors.lastname: Weih
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Freytag
authors.affiliation: Signal Transduction Laboratory, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Departments of Pathology & Cell Biology and Microbiology & Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
authors.affiliation: Research Group Genomic Stability, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Research Group Immunology, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D061167:Central Tolerance / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6
keywords: Autoimmunity; Central immune tolerance; Conditional gene targeting; Medullary thymic epithelial cells; NF-κB