Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33-45

Division of Developmental Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2005; 202(1):33-45. DOI: 10.1084/jem.20050471
Source: PubMed

ABSTRACT 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 CD80(hi) 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.

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Available from: Benedikt Brors, Sep 26, 2015
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    • "Among Aire-induced transcripts, 21 (23.9%) were classified as TRAs according to previously used criteria and manual scoring (Table S1; Derbinski et al., 2005). Thus, unlike the reported Aire-dependent transcriptomes of mTECs or eTACs (Anderson et al., 2002; Derbinski et al., 2005; Gardner et al., 2008), Aire-induced genes in thymic B cells are not enriched in TRAs compared to any random set of genes (around 25%) (Anderson et al., 2002; Gardner et al., 2008). Expression analyses of representative TRAs (Grik2, expressed in the brain; Ggn, spermatocytes; Lamp3, lung) confirmed that their mRNA levels correlated with the expression of Aire (Figure 1H). "
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    ABSTRACT: Thymic antigen-presenting cells (APCs) such as dendritic cells and medullary thymic epithelial cells (mTECs) use distinct strategies of self-antigen expression and presentation to mediate central tolerance. The thymus also harbors B cells; whether they also display unique tolerogenic features and how they genealogically relate to peripheral B cells is unclear. Here, we found that Aire is expressed in thymic but not peripheral B cells. Aire expression in thymic B cells coincided with major histocompatibility class II (MHCII) and CD80 upregulation and immunoglobulin class-switching. These features were recapitulated upon immigration of naive peripheral B cells into the thymus, whereby this intrathymic licensing required CD40 signaling in the context of cognate interactions with autoreactive CD4(+) thymocytes. Moreover, a licensing-dependent neo-antigen selectively upregulated in immigrating B cells mediated negative selection through direct presentation. Thus, autoreactivity within the nascent T cell repertoire fuels a feed forward loop that endows thymic B cells with tolerogenic features. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 06/2015; 42(6). DOI:10.1016/j.immuni.2015.05.013 · 21.56 Impact Factor
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    • "The relative levels of HLA-DR expression on mTECs correlate with their maturation stage. Mature HLA-DR hi AIRE þ mTECs are responsible for expression of most TRAs in the thymus [25]. Hence we mapped the expression of SEMG1 and CNTN2 to FACS-purified HLA-DR lo (immature) and HLA-DR hi (mature) mTECs. "
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    ABSTRACT: Promiscuous gene expression (pGE) of tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTECs) is in part driven by the Autoimmune Regulator gene (AIRE) and essential for self-tolerance. The link between AIRE functional mutations and multi-organ autoimmunity in human and mouse supports the role of pGE. Deep sequencing of the transcriptome revealed that mouse mTECs potentially transcribe an unprecedented range of >90% of all genes. Yet, it remains unclear to which extent these low-level transcripts are actually translated into proteins, processed and presented by thymic APCs to induce tolerance. To address this, we analyzed the HLA-DR-associated thymus peptidome. Within a large panel of peptides from abundant proteins, two TRA peptides were identified: prostate-specific semenogelin-1 (an autoantigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome) and central nervous system-specific contactin-2 (an autoantigen in multiple sclerosis). Thymus expression of both genes was restricted to mTECs. SEMG1 expression was confined to mature HLA-DR(hi) mTECs of male and female donors and was AIRE-dependent, whereas CNTN2 was apparently AIRE-independent and was expressed by both populations of mTECs. Our findings establish a link between pGE, MHC-II peptide presentation and autoimmunity for bona fide human TRAs. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Autoimmunity 04/2015; 60. DOI:10.1016/j.jaut.2015.03.004 · 8.41 Impact Factor
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    • "In the thymus, medullary thymic epithelial cells (mTECs) are able to express TRAs in order to mediate negative selection. Two alternative (extreme) modes of how TRAs might be presented in the thymus are under discussion [1] [5] [8]. According to the details of their respective genetic mechanisms, they are known as developmental model and terminal differentiation model, respectively, in the biological literature, but we would like to call them emulation model and mixture model, respectively, for the sake of the immediate intuitive appeal to the nonspecialist. "
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    ABSTRACT: We present an application of rare event simulation in the area of immune biology. A major task of the immune system is the recognition of foreign antigens, which enter the body as parts of invaders like bacteria or viruses. This task is performed by T-cells, specialised white blood cells, which are trained to distinguish foreign from self molecules and to start a specific immune response against an invader upon detection. The T-cells face an enormous challenge since the foreign antigens are few, and they must be discerned against a large fluctuating background of (harmless) self antigens. They meet this challenge with the help of a large, but restricted, number of different T-cell receptor types as well as a maturation process known as negative selection. Van den Berg et al. [21] presented the first version of a T-cell model that takes the probabilistic nature of foreign-self discrimination into account. They modelled the encounter of a T-cell with an antigen-presenting cell (APC; another type of white blood cell) in terms of sums of i.i.d. random variables that represent the stimulation rates emerging from the antigens displayed on the APC surface. The crucial quantity then is the activation probability of the T-cell, i.e., the probability that the sum G(z f) of stimulation rates exceeds a certain activation threshold gact, where z f is the copy number of the foreign antigen type. As T-cell activation is a rare event, analysis of biologically meaningful activation proba-bilities P(G(z f) ≥ gact) requires efficient simulation approaches. For this purpose, Lipsmeier et al. [10] developed an asymptotically efficient simulation approach based on large deviation theory and taylored to this specific model. Including negative selection into the model turns the crucial quantity into the conditional activation probability P(G(z f) ≥ gact|Ω), where Ω denotes the event of survival of negative selection. In contrast to previous approaches, this requires individual-based T-cell modelling and simulation. We develop a corresponding simulation method and explore the resulting ability of foreign-self distinction. More precisely, we investigate the effects of two contrasting modes of antigen presentation during the selection process, namely so-called promiscuous presentation and presentation in tissue-specific subsets [3].
    10th International Workshop on Rare Event Simulation, Amsterdam; 08/2014
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