CRC 1453 Seminar Series - Distinguished Speaker Professor Friedhelm Hildebrandt – Harvard Medical School; Boston Children’s Hospital
Topic: Precision Medicine in Early-Onset Chronic Kidney Disease
The focus of our lab is to understand the role of transcription factors in lymphocyte development and function. Ultimately this analysis will lead to the identification of new regulatory pathways, which can be translated into clinical practice. Thus our lab has a strong interest in basic immunology while at the same time trying to transfer knowledge from “bench to bedside”.
The developmental program and the effector function of different lymphocyte subsets are determined by transcription factors, which coordinate a regulated program of gene expression. This in turn implicates that the differential expression or the specific combination of transcription factors can serve as a hallmark for different lymphocyte subsets. How transcription factors can have such lineage defining capacity is one of the major challenges in biology.
T-box Transcription Factors in Innate and Adaptive immunity
NK cells and CD8 T cells are both cytotoxic and efficient cytokine producers upon activation; hence it is reasonable to assume that these functions are controlled by the same set of genes. In fact NK cells and CD8 effector T cells both express high levels of the T-box transcription factors T-bet and Eomesodermin (Eomes) that are defined by their evolutionary highly conserved T-box binding domain. T-bet is the master regulator of T helper 1 cell commitment in CD4 T cells, however primed CD8 T cells from T-bet knockout mice show normal cytotoxicity and IFN-γ production as compared to wild type. In this case Eomes can compensate for T-bet as inhibition of both factors severely impaired cytotoxicity and cytokine production. Similar redundancy has been observed in NK cells from T-bet knockout mice, which show only a modest reduction in cytotoxicity and cytokine production. Nevertheless recent evidence suggests that the two factors are not always interchangeable as T cell specific Eomes knockout mice fail to generate competitive CD8 memory T cells indicating that the two transcription factors also have exclusive targets.
Using transcription factor specific reporter mice in combination with constitutive and conditional knockout mice we want to get a detailed understanding of the spatial and temporal induction of these transcription factors to unravel their distinct roles in different lymphocyte subsets.
FoxP3, Regulatory T Cells (Tregs) and Transplantation Tolerance
Transplantation has been a very successful approach for the treatment of end stage organ failure and is frequently a life-saving operation. However the necessity for long-term immunosuppression with its myriad toxicities and long-term side effects is one of the major obstacles transplantation medicine faces at the moment.
The avoidance of any permanent immunosuppression by promoting a state of tolerance could help to increase the number of patients benefiting from this most ?physiological“ treatment while at the same time prolonging the survival of transplanted organs. We want to address this challenge by using Tregs. Tregs are defined by the master transcription factor FoxP3. They maintain immunological self tolerance, play a key role in the structural organization of an immune response and myriad attempts have been made to harness their suppressive capacities. We are one of a few labs in the world, which are able to keep regulatory T cells in culture for extended periods (> 12 months). Using different methods to genetically modify these Tregs or to induce them de novo we will test their ability to promote transplantation tolerance in an allo-antigen specific manner.