Division of Developmental Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):E3497-505. doi: 10.1073/pnas.1308311110. Epub 2013 Aug 26.
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.
多种组织特异性自身抗原（TRAs）在髓质胸腺上皮细胞（mTECs）中的杂乱表达对于维持自身耐受至关重要。杂乱基因表达的一个显著特征是其镶嵌模式（即，在给定的时间内，每个自身抗原仅在 1-3%的 mTECs 中表达）。目前尚不清楚这种镶嵌模式如何在单细胞水平上产生。在这里，我们表明表达特定 TRA 的人 mTEC 亚群共同表达不同的基因集。我们确定了三个共表达组，包含重叠和互补的基因集，这些基因集优先映射到特定的染色体和染色体内基因簇上。共表达基因座倾向于在同一核亚域中聚集。TRA 亚群沿着成熟 mTEC 亚群中的逐步分化阶段排列，并且在体外，它们沿着这个序列相互转换。我们的数据表明，单个 mTEC 会通过不同的基因库进行转移，从而扫描大量杂乱表达的自身抗原的整体库。这些发现对诱导耐受时髓质中自身抗原的时空（再）呈现具有重要意义。
