Thymic expression of tissue-restricted self-antigens is a highly coordinated and evolutionary conserved process

Abstract

Abstract Promiscuous gene expression (pGE) of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for tolerance imposition in the thymus. PGE is characterized on the one hand by inclusion of a broad range of TRAs and on the other hand by its mosaic patterns, whereby each antigen is only expressed in 1–3% of mTECs at a given point in time. Yet, this mosaic pattern at the single cell level faithfully adds up to the full repertoire of self-antigens at the population level. In order to analyze the regulatory mechanisms underlying this transcriptional heterogeneity among mTECs, we applied two complementing approaches, the isolation of minor mTEC subsets as defined by TRA-selected gene co-expression groups in conjunction with single cell mRNA sequencing. Different TRA-selected mTEC subfractions, each expressing distinct sets of genes in a mutually overlapping fashion, mapped to distinct stages of mTEC development. These co-expression patterns were evolutionary conserved between mouse and human (Rattay et al., J. Autoimmunity 2015). Applying an unbiased single cell mRNA sequencing approach, we extended these findings to the single cell level and showed that the mouse mTEC population essentially represents a composite of multiple co-expression groups (Brennecke et al., Nat. Immunology 2015). These co-expression groups may represent only snapshots of a continuum of changing co-expression groups along the lifetime of an individual mTEC, as captured in the model of “sliding co-expression groups” (Pinto et al., PNAS 2013). Continuous genome scanning would potentially enlarge the overall diversity of self-antigens displayed by a single mTEC.