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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: 13.91). 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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    • "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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    • "The observation that mutations in the Aire gene are associated with severe, multi-organ, tissue-specific autoimmunity in both humans and mice and the use of KO mouse model systems identified the role this gene plays in controlling central tolerance (Björses et al. 2000; Derbinski et al. 2005; Kont et al. 2008; Nagamine et al. 1997; Ramsey et al. 2002; Su and Anderson 2004; Su et al. 2008). "
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