Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity

• Verfasst von: Pinto, Sheena Dominique [VerfasserIn]
• Verfasst von: Michel, Chloé [VerfasserIn]
• Verfasst von: Schmidt-Glenewinkel, Hannah [VerfasserIn]
• Verfasst von: Harder, Nathalie [VerfasserIn]
• Verfasst von: Rohr, Karl [VerfasserIn]
• Verfasst von: Wild, Stefan [VerfasserIn]
• Verfasst von: Brors, Benedikt [VerfasserIn]
• Verfasst von: Kyewski, Bruno [VerfasserIn]
• Titel: Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity
• Verf.angabe: Sheena Pinto, Chloé Michel, Hannah Schmidt-Glenewinkel, Nathalie Harder, Karl Rohr, Stefan Wild, Benedikt Brors, and Bruno Kyewski
• E-Jahr: 2013
• Jahr: August 26, 2013
• Umfang: 9 S.
• Fussnoten: Gesehen am 24.11.2021
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2013
• Band/Heft Quelle: 110(2013), 37, Seite E3497-E3505
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1308311110
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: central tolerance
• Sach-SW: human thymic epithelial cells
• Sach-SW: promiscuous gene expression
• K10plus-PPN: 1778928994

Abstract

Promiscuous expression of numerous tissue-restricted self-antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential to safeguard self-tolerance. A distinct feature of promiscuous gene expression is its mosaic pattern (i.e., at a given time, each self-antigen is expressed only in 1-3% of mTECs). How this mosaic pattern is generated at the single-cell level is currently not understood. Here, we show that subsets of human mTECs expressing a particular TRA coexpress distinct sets of genes. We identified three coexpression groups comprising overlapping and complementary gene sets, which preferentially mapped to certain chromosomes and intrachromosomal gene clusters. Coexpressed gene loci tended to colocalize to the same nuclear subdomain. The TRA subsets aligned along progressive differentiation stages within the mature mTEC subset and, in vitro, interconverted along this sequence. Our data suggest that single mTECs shift through distinct gene pools, thus scanning a sizeable fraction of the overall repertoire of promiscuously expressed self-antigens. These findings have implications for the temporal and spatial (re)presentation of self-antigens in the medulla in the context of tolerance induction.