Abstract
To induce central T‐cell tolerance, medullary thymic epithelial cells (mTEC) collectively express most protein‐coding genes, thereby presenting an extensive library of tissue‐restricted antigens (TRAs). To resolve mTEC diversity and whether promiscuous gene expression (PGE) is stochastic or coordinated, we sequenced transcriptomes of 6,894 single mTEC, enriching for 1,795 rare cells expressing either of two TRAs, TSPAN8 or GP2. Transcriptional heterogeneity allowed partitioning of mTEC into 15 reproducible subpopulations representing distinct maturational trajectories, stages and subtypes, including novel mTEC subsets, such as chemokine‐expressing and ciliated TEC, which warrant further characterisation. Unexpectedly, 50 modules of genes were robustly defined each showing patterns of co‐expression within individual cells, which were mainly not explicable by chromosomal location, biological pathway or tissue specificity. Further, TSPAN8+ and GP2+ mTEC were randomly dispersed within thymic medullary islands. Consequently, these data support observations that PGE exhibits ordered co‐expression, although mechanisms underlying this instruction remain biologically indeterminate. Ordered co‐expression and random spatial distribution of a diverse range of TRAs likely enhance their presentation and encounter with passing thymocytes, while maintaining mTEC identity.
Highlights
To induce central T-cell tolerance, medullary thymic epithelial cells collectively express most protein-coding genes, thereby presenting an extensive library of tissue-restricted antigens (TRAs)
We chose to analyse the transcriptomes of single medullary thymic epithelial cells (mTEC) that were unselected or that promiscuously expressed either tetraspanin 8 (TSPAN8) or glycoprotein 2 (GP2) (Sansom et al, 2014; Rattay et al, 2016) with the aim of adding statistical power to co-expression analyses
The molecular processes underlying promiscuous gene expression (PGE) in single mTEC have remained unclear despite numerous studies addressing this topic. These studies, which have been limited by technology and cell number, have not established conclusively whether tissue-restricted genes (TRGs) expression in single mTEC is stochastic or ordered (Derbinski et al, 2005, 2008; Villasenor et al, 2008; Pinto et al, 2013; Sansom et al, 2014; Brennecke et al, 2015; Meredith et al, 2015; Rattay et al, 2016)
Summary
To induce central T-cell tolerance, medullary thymic epithelial cells (mTEC) collectively express most protein-coding genes, thereby presenting an extensive library of tissue-restricted antigens (TRAs). Thymic epithelial cells (TEC), the major stromal cell constituent of the thymus (Barthlott et al, 2006; Takahama, 2006; Abramson & Anderson, 2017), express almost the entire protein-coding genome (Sansom et al, 2014; Brennecke et al, 2015) and harbour an increased risk of transdifferentiation and losing cellular identity This capacity includes the competence to transcribe tissue-restricted genes (TRGs) whose expression in the periphery is normally limited to a single or small subset of tissues and genes whose expression is temporally or developmentally controlled or is sex-specific (Derbinski et al, 2001; Kyewski & Klein, 2006). TSPAN8 is expressed in the gastrointestinal tract and several carcinomas (Agaesse et al, 2017; Zhu et al, 2017; Zhao et al, 2018), and GP2 is expressed in the pancreas and gastrointestinal tract (Ohno & Hase, 2010; Cogger et al, 2017); loss of tolerance to GP2 is associated with Crohn’s disease and primary sclerosing cholangitis (Werner et al, 2013; Tornai et al, 2018)
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