1. Central immune tolerance depends on crosstalk between the classical and alternative NF-κB pathways in medullary thymic epithelial cells
- Author
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Marc Riemann, Elke Meier, Helga Freytag, Debra Weih, Falk Weih, Nico Andreas, Maria Fedoseeva, Ulf Klein, Ruth Schmidt-Ullrich, and Zhao-Qi Wang
- Subjects
0301 basic medicine ,Cancer Research ,T-Lymphocytes ,Immunology ,Gene Expression ,Autoimmunity ,Mice, Transgenic ,Thymus Gland ,Biology ,NF-κB ,Conditional gene targeting ,Medullary thymic epithelial cells ,Central immune tolerance ,medicine.disease_cause ,Immune tolerance ,Cell Line ,03 medical and health sciences ,Negative selection ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Transcription (biology) ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Animals ,Transcription factor ,Lung ,Mice, Knockout ,TNF Receptor-Associated Factor 6 ,RELB ,NF-kappa B ,Cell Differentiation ,Epithelial Cells ,Dendritic Cells ,Crosstalk (biology) ,030104 developmental biology ,chemistry ,Liver ,Central Tolerance ,Cancer research ,030215 immunology ,Signal Transduction - 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-{kappa}B transcription factor subunit RelB, which is activated by the alternative NF-{kappa}B 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-{kappa}B subunits RelA and c-Rel, which are both activated by classical NF-{kappa}B 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-{kappa}B pathways that tightly controls the development of mature mTECs to ensure self-tolerance.
- Published
- 2017