title: Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity.
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.
authors: Division of Developmental Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Sheena
authors: S
authors: Pinto
authors: Chloé
authors: C
authors: Michel
authors: Hannah
authors: H
authors: Schmidt-Glenewinkel
authors: Nathalie
authors: N
authors: Harder
authors: Karl
authors: K
authors: Rohr
authors: Stefan
authors: S
authors: Wild
authors: Benedikt
authors: B
authors: Brors
authors: Bruno
authors: B
authors: Kyewski
mesh_terms: D000940:Antigenic Variation; D001324:Autoantigens / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000145:classification / Q000166:cytology / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D005810:Multigene Family; D017634:Self Tolerance / Q000235:genetics; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D001324:Autoantigens
keywords: central tolerance; human thymic epithelial cells; promiscuous gene expression
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