Division of Developmental Immunology
Prof. Dr. Bruno Kyewski
Self/non-self discrimination is a hallmark of the immune system of multi-cellular organisms. The thymus of higher vertebrates plays a central role in the induction of T cell tolerance (“central tolerance”). During self-tolerance induction, the highly diverse T cell receptor repertoire is probed against an unknown array of self-antigens mirroring the “immunological self” of the body. These interactions rid the repertoire of auto-reactive T cells. Our discovery of promiscuous gene expression (pGE) and its essential function in preventing organ-specific autoimmunity has led to a reappraisal of the role of central tolerance in self/non-self discrimination. The diversity of self-ligands in the thymus is to a large extent generated by ectopic expression of numerous tissue-restricted antigens in medullary thymic epithelial cells (mTECs). This gene pool encompasses > 10 % of all known genes and represents virtually all tissues of the body. Promiscuous gene expression allows self-antigens, which otherwise are expressed in a spatially or temporally restricted manner, to become continuously accessible to developing T-cells thus rendering them tolerant. Specific failure of promiscuous gene expression can lead to severe organ-specific autoimmune diseases like type 1 diabetes mellitus. This gene pool also includes tumor-associated antigens, thus imposing immunological tolerance towards tumors, a fact to be considered in the selection of tumor antigens for clinical vaccination trials.
PGE represents one of the most fascinating and arcane aspects of T cell tolerance. In future we will further pursue our studies on the cellular and molecular regulation of this phenomenon in experimental in vitro and in vivo models. In particular, we would like to understand how a terminally differentiated epithelial cell type generates such a diverse self-antigen repertoire in a mosaic fashion such that the expression patterns of individual mTECs faithfully add up to the full complement of self-antigens at the population level. In this context we will search for rules, which guide the selection of promiscuously expressed genes in mTECs at the single cell and population level. We expect the different but complementing avenues of inquiry to provide us with a more comprehensive understanding of the functional organization of the thymic- microenvironment in the context of self-tolerance and new insights into gene (co)-regulation in case of pGE and beyond. In addition, we will continue to directly apply our findings in basic research to human disorders, i.e. further explore the interrelationship between pitfalls of pGE and human autoimmune diseases and identify underlying molecular mechanisms controlling the intra-thymic expression of prominent auto-antigens. Finally we will exploit our acquired knowledge on the biology of human thymic epithelial cells to develop new diagnostic markers for different human thymoma subtypes.
Giraud, M., Taubert, R., Vandiedonck, C., Ke, X., Levi-Strauss, M., Pagani, F., Baralle, F. E., Eymard, B., Tranchant, C., Gajdos, P., et al. (2007). An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature, 448, 934-937
Klein, L., Hinterberger, M., Wirnsberger, G. & Kyewski, B. (2009). Antigen presentation in the thymus for positive selection and central tolerance induction. Nat. Rev. Immunol., 9, 833-844
Tykocinski, L. O., Sinemus, A., Rezavandy, E., Weiland, Y., Baddeley, D., Cremer, C., Sonntag, S., Willecke, K., Derbinski, J. & Kyewski, B. (2010). Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. Proc. Natl. Acad..Sci. U S A, 107, 19426-19431
Lv, H., Havari, E., Pinto, S., Gottumukkala, R. V., Cornivelli, L., Raddassi, K., Matsui, T., Rosenzweig, A., Bronson, R. T., Smith, R., et al. (2011). Impaired thymic tolerance to alpha-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest., 121, 1561-1573