The thymus is a primary lymphoid organ, which is responsible for the development and selection of mature, naïve T lymphocytes, which eventually will seed the peripheral lymphoid organs.Thymic epithelial cells are critically involved in these differentiation and selection processes e.g. they are indispensable for negative selection of auto-reactive T cells thus ensuring immunological self-tolerance. Defects of proper development, maturation or maintenance of TECs can thus lead to severe immune deficiency or autoimmune diseases. Malignant tumours of the thymic epithelium (thymomas) are often associated with autoimmunity.
TECs fall into two major lineages (cortical and medullary TECs), but their origin and lineage commitment is not completely understood. Recently, we identified bipotent thymic epithelial stem cells in mice, which can give rise to both lineages in vitro and in vivo (for further details see Ucar et al. 2014. Immunity 41, 257-69). We willextend these studies and isolate and characterize human thymic epithelial stem cells and their malignant counterparts - cancer stem cells of human thymomas.
The project is based on the isolation of epithelial stem cell via the sphere assay. The stem cell candidates will be characterized by analysis of surface markers, immunochemistry as well as transcriptional profiling. The developmental potential of these putative progenitor cells in vitro will be assessed in thymic organ cultures. The project involves various approaches, e.g. ex vivo cell isolation methods, cell purification and phenotype characterization by flow cytometry (FACS), in vitro cell and organ culture and transplantation assays, advanced imaging analysis, single cell transcriptome analysis, and bio-informatic data analysis.
Further reading: Weis et al. 2015. J. Thoracic Oncol.; Kianizad et al. 2014. Immunity 41, 675; Klein et al 2014. Nat. Rev. Immunol. 14, 377.
We are looking for a highly motivated and enthusiastic applicant with a strong background in cell/molecular/developmental biologyor related areas,basic knowledge in immunology is advantageous. The applicant will conduct high-level basic research in the field of stem cell biology/immunology in a small dynamic team. The experimental part of the project will be split between the Department of Pathology, Medical Faculty, University of Mannheim (Prof. A. Marx) and the Division of Developmental Immunology at the German Cancer Research Center in Heidelberg (Prof. B. Kyewski).
The German Cancer Research Center is the largest biomedical research center in Germany hosting all state-of-the-art methodology and close collaborations with various clinical departments.
The position is open immediately and paid initially for 2 years by an institutional grant of the Medical Faculty of the University of Mannheim with the possibility of further extension.
Master Student in Bioinformatics
The group of Prof. Bruno Kyewski at the DKFZ studies an essential feature of the immune system, i.e. its ability to discriminate between self and non-self. If this mechanism becomes leaky, it can result in autoimmune diseases. The naïve T cells are tolerized to self-antigens within the primary lymphoid organ, the “thymus”. A type of thymic epithelial cells (mTECs) have the unique ability to express a wide array of genes that are otherwise exclusively expressed in other body cells. This “promiscuous” gene expression (pGE) displays two prominent features: the genes are highly clustered in the genome and show a preference for tissue-restricted antigens.
We currently study the evolutionary conservation of pGE and its molecular regulation.To this end we performed (i) genome-wide arrays in mouse, rat and human cells and (ii) extensive single cell gene expression analysis yielding complex co-expression patterns. Our preliminary bioinformatic analysis proceeded from the definition of TRA clusters, gene clustering and homology mapping. Future studies will address evolutionary mechanisms responsible for selecting this gene pool and defining the boundaries of these gene clusters. Conceivably, positional cues in the genome (i.e. global regulators/insulators) could have been driving forces during the co-evolution of pGE and adaptive immunity.
To support the bioinformatic part of this project we are looking for a highly motivated, diligent and enthusiastic applicant with a strong background in programming (R and Perl) and an interest in immunology.
For further information kindly contact:
Prof. Bruno Kyewski, Phone:+49 6221 42 3734, E-mail: firstname.lastname@example.org
Dr. Sheena Pinto, Phone:+ 49-6221 42 3781, E-mail: email@example.com