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Promiscuous Gene Expression in Thymic Epithelial Cells Is Regulated

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ARTICLE Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels Jens Derbinski,1 Jana Gäbler,1 Benedikt Brors,2 Sascha Tierling,6 Sunitha Jonnakuty,3 Manfred Hergenhahn,4 Leena Peltonen,5 Jörn Walter,6 and Bruno Kyewski1 1Division of Developmental Immunology, 2Division of Theoretical Bioinformatics, 3Division of Molecular Biophysics, and 4Division of Genetic Alterations in Carcinogenesis, German Cancer Research Center, D-69120 Heidelberg, Germany 5Department of Medical Genetics, University of Helsinki, 00029 HUS, Helsinki, Finland 6Department of Genetics, Saarland University, D-66041 Saarbrücken, Germany The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80hi mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and –independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance. CORRESPONDENCE Self-tolerance is inextricably linked to immunity; an inherent property of the thymic stroma has Bruno Kyewski: only when both features of the immune system been established by studies reporting the tran- [email protected] are balanced is the body’s integrity safeguarded. scription of genes coding for proteins that serve Abbreviations used: Aire, Our perception of how self-tolerance of the cell type–specific functions; e.g., proteolipid protein autoimmune regulator; ANOVA, plethora of self-antigens is initially imposed and (PLP) in oligodendrocytes or interphotoreceptor analysis of variance; Cdkn1c, maintained throughout life has recently changed. retinoid binding protein in retinal cells (3, 4). cyclin-dependent kinase inhibitor The Journal of Experimental Medicine 1C; cTEC, cortical TEC; H19, Two areas of research, initially pursued indepen- Although promiscuous gene expression by thy- H19 fetal liver mRNA; Igf2, dently but which now converge, contributed to mic epithelial cells (TECs) in various species is insulin-like growth factor 2; LOI, this development. First, the observation was by now undisputed, many aspects of this phe- loss of imprinting; mTEC, made that a diverse array of tissue-restricted anti- nomenon remain to be explored. Thus, the medullary TEC; SNuPE, single nucleotide primer extension; gens (TRAs) is expressed in the thymus and dis- complete scope of promiscuously expressed TEC, thymic epithelial cell; played there for repertoire selection (1). Second, genes is unknown. An initial expression analysis Tlbp; testis lipid binding protein; unambiguous experimental evidence emerged focused on selected self-antigens including TRA, tissue-restricted antigen. that dominant tolerance mechanisms, foremost many prominent autoantigens (5). Two recent CD4 regulatory T cells, are essential rather than reports in mice and humans, however, indicate supplementary to recessive tolerance modes such that this gene pool is broadly inclusive rather as deletion (2). These new insights, apart from than selective (6, 7). A comprehensive analysis their conceptual implications, also open new of promiscuously expressed genes will delineate therapeutic possibilities, not least for the treat- the ultimate extent of tissue representation in the ment of autoimmune diseases. thymus and possibly offer new clues as to the The notion that aberrant expression of underlying molecular regulation. TRAs (termed promiscuous gene expression) is Particular features of promiscuous gene ex- pression (i.e., being uncoupled from tissue or The online version of this article contains supplemental material. developmental regulation) appear unique among JEM © The Rockefeller University Press $8.00 33 Vol. 202, No. 1, July 4, 2005 33–45 www.jem.org/cgi/doi/10.1084/jem.20050471 somatic cells, suggesting a novel mode of molecular regula- from failures of multiple endocrine organs and show height- tion. An important initial clue as to this regulation has been ened autoantibody titers to organ-specific self-antigens (9, the finding that the autoimmune regulator (Aire) controls 10), most of which are promiscuously expressed in human the expression of numerous genes in murine medullary mTECs (7). Based on these particular features of APS-1, the TECs (mTECs) with a predilection for TRAs (6). This im- functional properties of Aire as a transcriptional coregulator portant finding offers a cogent explanation for the patho- and its conspicuous overexpression in mTECs, we had pre- physiology of the monogenic human autoimmune polyglan- viously proposed a role for Aire in controlling promiscuous dular syndrome 1 (APS-1), which is caused by mutations in gene expression (11). With Aire influencing intrathymic ex- the AIRE gene (8). APS-1 patients suffer to various degrees pression of numerous TRAs in a dose-dependent manner Figure 1. Global analysis of promiscuous gene expression in the highest proportion (106 out of 150) of differentially expressed genes. distinct thymic stromal cells. (A) Quantitative analysis of differentially Yellow, up-regulated genes; blue, down-regulated genes; black, approxi- expressed genes in mutual comparisons between mTECs and cTECs, DCs, mately the same gene expression as the mean for that gene across all and macrophages based on Affymetrix microarray analysis. The black bars samples. Numbers beside the color key represent mean SD of the indicate the fraction of TRAs contained in all genes overexpressed in the respective gene. (C) Diverse tissue representation by genes overexpressed respective subsets and the relative percentages of TRAs are indicated in mTECs vs. cTECs. (D) The reverse gene set shows limited tissue represen- above the bars. (B) ANOVA of all four stromal cell subsets showing the top tation. Genes were assigned to tissues according to their predominant 150 probe sets with adjusted p-values of Ͻ0.01. Note that mTECs display expression (Materials and methods). Mo, macrophages. 34 REGULATION OF THYMIC PROMISCUOUS GENE EXPRESSION | Derbinski et al. ARTICLE (12), it becomes apparent that the regulation of Aire itself probably because of the fact that the array analysis is less sen- will be an important determinant in self-tolerance control. sitive than RT-PCR and that promiscuously expressed The lymphotoxin ␤ receptor has been recently identified as genes are often expressed at low levels. To validate our crite- one upstream component of this molecular pathway (13). ria for the identification of overexpressed genes, we analyzed Promiscuous gene expression, however, cannot solely be the expression of several mTEC-specific genes identified accounted for by the action of this molecule. The contribu- with the microarray analysis by real-time PCR. Certain tion of additional mechanisms is clearly documented by the “marker genes” for mTECs were reliably confirmed, and we fact that transcription levels of tissue-restricted antigens are therefore regarded the chosen criteria as valid. Casein ␤ and dependent on Aire to various degrees, with some genes not the testis lipid binding protein (Tlbp) are detectable at equal lev- being influenced by Aire at all (e.g., CRP or GAD67; refer- els in mTECs of both genders, including nonlactating female ence 6). The complexity of the regulation of promiscuous mice. (Fig. S1, available at http://www.jem.org/cgi/con- gene expression is further exemplified by differences in cell tent/full/jem.20050471/DC1, and not depicted). Thus, type–specific expression patterns. The expression of certain promiscuous gene expression in mTECs overrides the nor- TRAs (e.g., GAD67) is restricted to mTECs, whereas others mal tissue-, sex-, and development-dependent gene regula- (e.g., thyroglobulin) are found in both cortical TECs tion of these two genes. Casein ␤ is typically induced late (cTECs) and mTECs at similar levels (14). To decipher the during pregnancy in the mammary gland (16), and Tlbp is apparently complex cellular and molecular regulation of pro- expressed in male germ cells (17). miscuous gene expression, we analyzed gene expression in Promiscuous expression has been operationally defined as distinct thymic stromal cell lineages and subsets thereof at the the expression of genes that so far have not been known to level of global gene expression and defined genomic regions. be part of the physiological gene expression program of thy- mic stromal cells. To apply more stringent criteria, we deter- RESULTS mined the percentage of genes with restricted tissue expres- MTECs specialize in promiscuous gene expression sion, a definition relying on
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