Diversity of genes and expression patterns

Diversity of genes and expression patterns

Scientists

Chloé Michel, Sheena Pinto, and Kristin Rattay

Project

Figure 2
© dkfz.de

Elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/non-self discrimination (1-2). This is largely attributable to the discovery of pGE. After the initial description of pGE based on expression of a selected set of TRAs (3,4), we performed a global mRNA expression analysis using whole genome arrays and deep sequencing. An intriguing finding of this analysis was the fact that pGE covers > 75 % of all genes, comprising of TRAs representing essentially all tissues of the body, irrespective of developmental, sex-specific or spatio-temporal expression patterns (Fig. 2). The encounter of potentially auto-reactive T cells with these TRAs in peripheral organs is already pre-empted in the thymus. This diverse expression pattern also offers an explanation for a long-standing puzzle, namely tolerance to self-antigens, which arise later in postnatal life long after the mature T cell repertoire has been established. These antigens include self-antigens of the reproductive tract (i.e. sperm-specific antigens), the placenta or the lactating mammary gland. Curiously, pGE also covers self-antigens specific to the opposite sex.

When probed at the single cell level by immuno-histochemistry, in situ hybridization or single cell PCR, in each case a particular TRA was only expressed in 1-3 % of all mTECs, equivalent to a few thousand cells per thymus. Nevertheless, these infrequent TRA-expressing cells were capable of efficiently purging the T cell repertoire of antigen-specific cells attesting to the efficacy of the tolerance process. Another notable finding was the significant genomic clustering of promiscuously expressed genes, which otherwise showed no structural or functional commonalities (5,6). Noteworthy, the level and diversity of pGE is unaltered in mTECs of the involuted thymus of aged mice and humans.  

Selected Publications

1. Kyewski, B. and J. Derbinski. 2004. Self-representation in the thymus: an extended view. Nat. Rev. Immunol. 4, 688-698.

2. Kyewski, B. and L. Klein. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24: 571-606.

3. Derbinski, J., A. Schulte, B. Kyewski and L. Klein. 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032-1039.

4. Gotter, J., B. Brors, M. Hergenhahn and B. Kyewski. 2004. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199:155-166.

5. Derbinski,J., J. Gäbler, B. Brors, S. Tierling, S. Jonnakuty, M. Hergenhahn, L. Peltonen, J. Walter, and B. Kyewski. 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33-45.

6. Pinto, S., C. Michel, H. Schmidt-Glenewinkel, N. Harder, K. Rohr, S. Wild, B. Brors, and B. Kyewski. 2013. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl. Acad. Sci. 110: E3497-E3505.

7. Brennecke, P. A. Reyes, S. Pinto, K. Rattay, M. Nguyen, R. Küchler, W. Huber, B. Kyewski, and L.M. Steinmetz. 2015. Single-cell transcriptome analysis reveals coordinated ectopic gene expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16:933-941.

8. Rattay, K., H.V. Meyer, C. Herrmann, B. Brors, and B. Kyewski. Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells.
J. Autoimmun. doi:10.1016/j.jaut.2015.10.001.

 

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