![]() Thus, phenotypically mature mTEC, i.e., those expressing high levels of CD80 and MHC class II ( 6), display the highest degree and diversity of pGE ( 8). The differentiation model holds that progressive differentiation of mTECs leads to a loss of repressive gene control mechanisms, which results in expression of diverse TRAs in an apparently stochastic manner. Two models are currently discussed to explain this unorthodox gene regulation. A role for epigenetic control is insinuated by the following observations ( i) promiscuously expressed genes tend to localize in clusters, ( ii) the imprinting status of Igf2 is lost in mTECs, ( iii) expression of certain TRAs including cancer germ cell antigens correlates with promotor hypomethylation (ref. Epigenetic mechanisms have been implicated but not yet directly addressed in detail. To date, the only known molecular factor identified to be involved in pGE is the autoimmune regulator ( Aire), which controls (to varying degrees) the expression of a large proportion of TRAs in mTECs. Thus, the temporal regulation during pre- and postnatal development or sex-specific expression patterns as observed in particular cell lineages are abolished in mTECs ( 8). PGE differs in basic aspects from tissue-specific gene regulation. Interestingly, pGE is apparently not restricted to the thymus but also operates in stromal cells of peripheral lymph nodes and thus might constitute a conserved feature between central and peripheral tolerance ( 7). Recessive (i.e., deletion) and dominant tolerance mechanisms (i.e., T reg induction/selection) cooperatively mediate tolerance toward TRAs ( 5, 6) thus, the immune system apparently does not discriminate between promiscuously and “conventionally” expressed self-antigens with respect to modes of tolerance induction. Thus, a defect in pGE of numerous self-antigens leads to a multiorgan autoimmune disease in man, known as autoimmune polyglandular syndrome (APS1) ( 2), and lack of promiscuous expression of even a single TRA can precipitate spontaneous, organ-specific autoimmunity in mice ( 3, 4). pGE appears necessary for preventing organ-specific autoimmune diseases in both species ( 1). pGE is foremost a physiological property of medullary thymic epithelial cells (mTECs) and is highly conserved between mouse and man. The apparent stochastic expression pattern of genes within the casein locus, the lower mRNA levels compared with mammary gland cells in conjunction with frequent coexpression of insulin in single mTECs clearly delineates the molecular mechanism(s) of promiscuous gene expression from cell lineage-specific gene control.Įxpression of tissue-restricted antigens (TRA) in the thymus, termed promiscuous gene expression (pGE), extends the scope of central T cell tolerance to virtually all tissues of the body. In contrast, coexpression of these genes in mature CD80 hi mTECs was rarely observed and no pattern of gene expression in individual mTECs was discernible. Mammary gland cells showed highly correlated intra- and interchromosomal coexpression of milk proteins (the casein genes, lactalbumin-α and whey acidic protein) and one of its transcriptional regulators ( Elf5). Here, we compared the expression profile of the casein gene locus in mTECs and mammary gland epithelial cells by single cell PCR. The molecular regulation of this unusual gene expression is not understood, in particular its delineation from cell lineage-specific gene expression control remains unclear. Promiscuous expression of tissue-restricted autoantigens in medullary thymic epithelial cells (mTECs) imposes central T cell tolerance. ![]()
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