Prof. Dr. Georg Holländer

Born 1957 Email: Georg-A.Hollaender@unibas.ch Studied Medicine at the University of Basel Trained clinically as a Board-certified paediatrician at the Children's Hospital, Harvard University, Boston, USA, and the Basel Children's Hospital. Postdoctoral research training in experimental immunology first at the Basel Institute for Immunology and then at the Dana-Farber Cancer Centre, Harvard Medical School. In 1994 appointed Instructor at Harvard University, and Assistant Professor in 1995. In 1996 established a research group in Basel at what is now the Department of Clinical-Biological Sciences focusing on the genetic control of thymus development and function. Since 1999 director of Research at the Basel Children's Hospital. Since 2003 full professor in Molecular Medicine in Paediatrics at the University of Basel. Past Research The development of new T cells is mainly restricted to the thymus where thymic epithelial cells represent the majority of stromal cells. Our past work has demonstrated that the normal architectural organisation and cellular composition of the stroma is instructed by cross-talk with developing T lymphocytes. For example, we demonstrated that mice deficient in early thymocyte maturation develop an abnormal thymic microenvironment unable to support normal T cell development. While such a defect can be corrected during fetal development, a reconstitution of the thymic microenvironment after birth completely fails demonstrating a critical time window during which regular thymus development can occur. Thymocyte differentiation in an aberrant thymic microenvironment generates a repertoire of T cells that mediate severe autoimmunity. Subsequent to these observations, work was focused on a better knowledge of the stromal requirements for the correct development of thymocytes using among other influences radiation, immuno-suppressants and graft-versus-host disease to test their impact on thymic function.   Current projects Our current research interests are aimed at defining the genetic programs that control thymic epithelial stem cells, their patterning and development along distinct lineages. Initially, several complementary methodological approaches have been used to identify the distinct signaling pathways associated with thymic epithelial fate commitment. Using laser capture microscopy and gene expression profiling, epithelial cells that had newly adopted a thymic cell fate were compared with the anatomically juxtaposed cells destined to develop into parathyroid epithelium. Based on these analyses, several differentially expressed gene products could be identified. Some of these belong to well-conserved signaling pathways whose utility and importance has previously been documented for the formation of other epithelial organs such as the lungs or the kidneys. Specifically, these and additional studies using transgenic gain-and-loss-of-function experiments have revealed that the Fgf, TGF-?/BMP/Activin, the Wnt and the hedgehog pathways play a critical role in the development of precursors to functionally competent thymic stromal cells. Work is now focused on the analysis of the genetic network operational during embryonic thymus development. Specifically, we address the following issues: What determines and controls the commitment of epithelia of the 3rd pharyngeal pouch to a thymus cell fate? How is the thymus epithelial cell identity maintained? How does a change in thymic epithelial cell function affect its ability to recruit lymphoid precursor cells and instruct their maturatiuon to functionally competent effector T cells?   Research within the Node   The focus of our contribution to C-CPHD is directed at a molecular, phenotypic and functional analysis of thymic epithelial stem cells (designated pTEC). Little is known regarding the characteristics of pTEC in the postnatal mouse. Although the functional competence of fetal pTECs to generate both cortical and medullary thymic epithelial cells (TECs) has recently been revealed for cells isolated from embryonic tissue, the equivalent potential has not been demonstrated for pTECs derived from adult mice. Furthermore, it remains unkown (although inferred from in vivo cell turn-over studies) whether an entire thymic microenvironment can be generated from single adult pTECs (as one would expect from stem cells). Our research group has recently demonstrated that an inducible albeit reversible, expression of Oct4 in TECs results in an expansion of progenitor cells while already differentiated TECs remain unaffected in their phenotype but display an inhibition of cell proliferation. Importantly, these cellular changes are completely reversible upon withdrawal of doxycycline (unpublished data). The mechanism by which ectopic Oct4 expression excludes multi-potent cells from differentiating is unknown but has been linked to activation of the Wnt/?-catenin cascade. The proposed research will focus on defining the genetic networks and epigenetic control of pTEC differentiation taking initially advantage of Oct4 expressing pTECs. Insight gained from these experiments will subsequently be used to probe the importance of specific gene expression patterns and epigenetic mechanisms for the in vivo development of pTECs using appropriate transgenic and gene-deletion mouse mutants.

Recent publications:

G. Holländer, B. Wang, A. Nichogiannopoulou, P. Plattenberg, E. VanEwijk, S.J. Burakoff, B-G. Guttierez-Ramos, C. Terhorst (1995) Developmentally restricted maturation of the thymic microenvironment required for normal T cell ontogeny. Nature, 373:350. G. Holländer, S. Zuklys, C. Morell, E. Mizoguchi, K. Mobisson, S. J. Simpson, C. Terhorst, W. Wishart, D. E. Golan, A. K. Bhan, S. J. Burakoff. (1998) Expression of the cytokine IL-2 is controlled by allelic exclusion. Science, 279: 2118. G. Balciunaite, M.P. Keller, E. Balciunaite, L. Piali, S. Zuklys, Y.S. Mathieu, J. Gill, R. Boyd, D.J. Sussman, G.A. Holländer (2002) Wnt glygoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nature Immunol., 3:1102-8. J. Gill, M. Malin, G.A. Holländer, R. Boyd (2002) Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nature Immunol., 3:635-42. Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, Werlen G, Holländer GA, Gascoigne NRJ, Palmer E.(2006) Thymic selection threshold defined by compartimentalization of Ras/MAPK signaling. Nature 444:724-9. Irla M, Hugues S, Gill J, Nitta T, Hikoska Y, Williams IR, Hubert FX, Scott HS, Takahama Y, Holländer GA, Reith W. (2008) Autoantigen-specific interactions with CD4+ thymocytes contro mature thymic epithelial cell cellularity. Immunity; 29:451-69.