Developmental Immunology

Division of Developmental Immunology

Prof. Dr. Bruno Kyewski

(A) The thymus is the site where central T cell tolerance is imposed. It consists of an outer cortex and a central medulla. The medulla is densely packed with various antigen-presenting cells, which present a plethora of self-antigens to developing T cells and thus induce self-tolerance. Medullary thymic epithelial cells (shown in red) have the unique property to express numerous tissue-restricted self-antigens in a promiscuous fashion and thus are essential for the prevention of autoimmunity. (B) Tissue representation of promiscuously expressed antigens by medullary thymic epithelial cells including embryonic and placental antigens.

Self/non-self discrimination is a hallmark of the immune system of multi-cellular organisms. The thymus of 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 molecular and cellular 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. Promiscuous gene expression signifies the unusual phenomenon that a plethora of tissue-restricted self-antigens are ectopically expressed in a particular cell type, medullary thymic epithelial cells (mTECs). This gene pool encompasses >85 % of all known genes and represents 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 of even a single self-antigen 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.

Promiscuous gene expression represents one of the most fascinating and arcane aspects of T cell tolerance. In the 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 are trying 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 found the mouse and human mTEC compartment to be a composite of numerous distinct coexpressed gene clusters with single mTECs displaying recurrent gene coexpression patterns. We expect the different and 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 (or lack thereof) of prominent auto-antigens. In the context of pGE, we also study the developmental biology of thymic epithelial cells, with the future aim to follow their full course of differentiation in vitro (using appropriate culture models) and in vivo from tissue-resident bi-potent stem cells to the terminally differentiated stage. Using a sphere assay we successfully identified and characterized a bi-potent TEC stem cell candidate of the embryonic and adult mouse thymus and we currently extend these findings to human TEC stem cells and their malignant counterparts, i.e. cancer stem cells in human thymomas. Finally, we will exploit our acquired knowledge on the biology of human thymic epithelial cells to develop new diagnostic tools for human thymoma subtypes.


Prof. Dr. Bruno Kyewski
Developmental Immunology (D090)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3734

Selected Publications

  • Kyewski, B., and L. Klein. (2006). A central role for central tolerance. Annu. Rev. Immunol. 24, 571-606.
  • Brennecke et al. (2015). Single-cell transcriptome analysis reveals coordinated ectopic gene expression patterns in medullary thymic epithelial cells. Nature Immunol, 16, 933-941.
  • 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.
  • Ucar, A., O. Ucar, P. Klug, S. Matt, F. Brunk, T.G. Hofmann, and B. Kyewski. 2014. The adult thymus contains FoxN1-negative epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41:257-269.
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