Developmental biology of thymic epithelial cells and thymomas

Developmental biology of thymic epithelial cells and thymomas

Scientists

Fabian Brunk, Paula Klug, Chloé Michel, Sheena Pinto, Olga Ucar

Project

Two major lineages constitute the TEC compartment of the vertebrate thymus, cortical (cTECs) and medullary TECs (mTECs). Both lineages originate from a common bipotent progenitor/stem cell in the fetal thymus and possibly also in the postnatal thymus. Committed cTECs and mTECs can be further subdivided into different differentiation stages according to different surface marker profiles. Thus, mTECs fall into two broad categories: immature CD80lowMHCIIlow and mature CD80highMHCIIhigh mTECs. Within the mature subset, the early stage does not express the transcriptional regulator Aire, while it is upregulated in the late, post-mitotic stage. Immature mTECs continuously give rise to mature mTECs thus leading to a steady-state turnover of mTECs which is about 3 weeks (1). Despite considerable progress in dissecting the developmental pathways of TECs and their molecular regulation, we still lack a complete roadmap of TEC differentiation spanning from the earliest bipotent/multipotent TEC stem cells to the terminal stages of both lineages. Thus, TEC stem cells and their immediate progeny, i.e. early post-committed mTECs and cTECs as well as the most terminal lineage stages, are still poorly characterized currently precluding their prospective isolation and characterization. In this regard we recently identified and isolated (i) a bipotent TEC stem cell (2), (ii) novel subsets of immature mTECs and (iii) late post-Aire mTECs. These various new subsets are currently being characterized with regard to their functional properties and precursor-product relationship. In parallel we developed an in vitro organotypic culture system, which mimics faithfully certain phases of mTEC differentiation (3). A particular focus is the role of the Wnt pathway in TEC biology. Despite the fact that Wnt signaling has been shown to be important for both TEC biology and T cell development, it has remained unclear, which cell type(s) display the primary source of Wnt ligands in the thymus and whether Wnt signaling acts via autocrine and/or paracrine signal transmission. We approach these issues both by expression analysis of various thymic cell types and by using genetic mouse models. 

The detailed dissection of the human TEC compartment allowed us for the first time to correlate human thymomas (i.e. TEC tumors) with defined stages of the mTEC and cTEC developmental pathways on the basis of their phenotype and molecular signature. This approach should eventually lead to a more precise classification of human thymoma subtypes.

Selected Publications

1. Gäbler, J., J. Arnold, and B. Kyewski. 2007. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells.Eur. J. Immunol. 37: 3363-3372.

2. 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

3. Pinto, S., K. Schmidt, S. Egle, H.-J. Stark, P. Boukamp, and B. Kyewski. 2013. An Organotypic Coculture Model Supporting Proliferation and Differentiation of Medullary Thymic Epithelial Cells and Promiscuous Gene Expression. J. Immunol.190: 1085-1093.

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