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Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters.

Gotter J, Brors B, Hergenhahn M, Kyewski B - J. Exp. Med. (2004)

Bottom Line: Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon.Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes.These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.

ABSTRACT
Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

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Thymic expression of tumor-associated antigens. Expression of selected tumor-associated antigens in thymic stromal cells of five thymi was assessed by RT-PCR. Expression in each case was confined to mTECs. Note interindividual variations and the difference in signal strength compared with control tissues. The amount of input cDNA was normalized according to signals obtained for GAPDH in a titration experiment (not depicted).
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fig2: Thymic expression of tumor-associated antigens. Expression of selected tumor-associated antigens in thymic stromal cells of five thymi was assessed by RT-PCR. Expression in each case was confined to mTECs. Note interindividual variations and the difference in signal strength compared with control tissues. The amount of input cDNA was normalized according to signals obtained for GAPDH in a titration experiment (not depicted).

Mentions: Expression of a second class of peripheral autoantigens, so called tumor-associated antigens, has been claimed to be absent from the thymus and the peripheral immune system and consequently thought to be exempted from self-tolerance (23, 24). We tested the expression pattern of four members of the cancer-germ line group (MAGE–A1, -A3, -A4, and NY-ESO-1) and two members of the group of melanoma differentiation antigens (MART-1 and tyrosinase), some of which had been selected for current clinical trials (25). Cancer-germ line antigens are expressed in male germ cells in uterus and various tumors and melanoma differentiation antigens in melanocytes and melanomas (26). All of these genes were detectable in purified mTECs, albeit with interindividual differences in their expression levels (Fig. 2) . Whereas MAGE-A1 was only detectable in one out of five thymi, MART-1 was present in all five samples. It is also notable that the expression levels were much lower than in the corresponding peripheral tissues. Notwithstanding these qualifications, the data show that tumor-associated antigens previously thought to be secluded from the immune system are also expressed by mTECs and thus presumably displayed to developing T cells. The selectivity of this expression in mTECs underpins the unique role this cell type plays in promiscuous gene expression. The high score with which “arbitrarily” selected genes were found to be expressed in mTECs and the diversity of these promiscuously expressed genes in mice and man implies that this gene pool is complex and comprehensive. To more precisely delineate this gene pool, we defined the transcriptome of these cell types by microarray analysis.


Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters.

Gotter J, Brors B, Hergenhahn M, Kyewski B - J. Exp. Med. (2004)

Thymic expression of tumor-associated antigens. Expression of selected tumor-associated antigens in thymic stromal cells of five thymi was assessed by RT-PCR. Expression in each case was confined to mTECs. Note interindividual variations and the difference in signal strength compared with control tissues. The amount of input cDNA was normalized according to signals obtained for GAPDH in a titration experiment (not depicted).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211762&req=5

fig2: Thymic expression of tumor-associated antigens. Expression of selected tumor-associated antigens in thymic stromal cells of five thymi was assessed by RT-PCR. Expression in each case was confined to mTECs. Note interindividual variations and the difference in signal strength compared with control tissues. The amount of input cDNA was normalized according to signals obtained for GAPDH in a titration experiment (not depicted).
Mentions: Expression of a second class of peripheral autoantigens, so called tumor-associated antigens, has been claimed to be absent from the thymus and the peripheral immune system and consequently thought to be exempted from self-tolerance (23, 24). We tested the expression pattern of four members of the cancer-germ line group (MAGE–A1, -A3, -A4, and NY-ESO-1) and two members of the group of melanoma differentiation antigens (MART-1 and tyrosinase), some of which had been selected for current clinical trials (25). Cancer-germ line antigens are expressed in male germ cells in uterus and various tumors and melanoma differentiation antigens in melanocytes and melanomas (26). All of these genes were detectable in purified mTECs, albeit with interindividual differences in their expression levels (Fig. 2) . Whereas MAGE-A1 was only detectable in one out of five thymi, MART-1 was present in all five samples. It is also notable that the expression levels were much lower than in the corresponding peripheral tissues. Notwithstanding these qualifications, the data show that tumor-associated antigens previously thought to be secluded from the immune system are also expressed by mTECs and thus presumably displayed to developing T cells. The selectivity of this expression in mTECs underpins the unique role this cell type plays in promiscuous gene expression. The high score with which “arbitrarily” selected genes were found to be expressed in mTECs and the diversity of these promiscuously expressed genes in mice and man implies that this gene pool is complex and comprehensive. To more precisely delineate this gene pool, we defined the transcriptome of these cell types by microarray analysis.

Bottom Line: Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon.Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes.These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.

ABSTRACT
Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

Show MeSH
Related in: MedlinePlus