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Project areas  / Project area B

Project area B: T cells and signaling

 

Since the molecular mechanisms of antigen processing are, in the meantime, very well known, we have now shifted our focus to other intracellular events. Accordingly, this area combines research on T cells, molecules involved in signaling in adaptive immunity, and the development of methods relevant for designing and assessing T-cell-mediated immunity, spanning immunoinformatics, structural biology, in vivo imaging of T-cell trafficking, NFκB and NFAT signaling, Th2 regulation, and signaling in lymphoma development.

 

 

  • Project B01, led by Oliver Kohlbacher, is now entirely focused on our needs for immunoinformatics. This will strengthen our attempts to develop tumor-specific immunotherapy by identifying and targeting mutated HLA ligands as T-cell epitopes. The selection of such epitopes is based on a wide range of complex data sets: next-generation sequencing of exomes (Exome-Seq) for the identification of tumor-specific genetic variations, next-generation RNA sequencing (RNA-Seq) for transcriptome analysis, HLA typing, LC-MS/MS data for HLA ligandome analysis, and several clinically relevant parameters. Due to the often rapidly deteriorating state of the patients, analysis and integration of these data sets has to be accomplished within a very short time frame, optimally within a few days of the availability of the data. In this project we will therefore develop, test, and validate the required algorithms for an integrative analysis of high-throughput data in order to ensure a timely selection of an optimal set of vaccine epitopes for each patient.

 

 

 

  • Project B03 (Stehle) represents our structural biology expertise. Thilo Stehle obtains structural and functional information about the interactions between viruses and cellular interaction partners, including cell surface receptors and immunoevasins. The results from our work during the last funding period established modes of interactions between measles virus, human cytomegalovirus, and human adenoviruses and their respective cellular receptors, explaining in several cases how viruses subvert the immune system. This has allowed us in one case to use the structural information to design a potent antiviral compound. We will expand on these results in the next funding period, focusing on immune evasion and the attachment and entry properties of human cytomegalovirus and adenovirus. In addition, we will pursue structural studies of the chitinase-like innate immune protein YKL-40 in collaboration with project A14 and of interleukin-1 receptor associated kinases in collaboration with project A15. Both projects will benefit from our documented expertise in structure-function studies of glycan processing and signaling molecules.

 

 

 

  • Project B06 (Pichler/Kneilling) developed T cell labeling protocols that allow the in vivo monitoring of T-cell homing patterns non-invasively by combined positron emission tomography (PET) and computed tomography (CT) or optical imaging (OI). PET/CT and OI unraveled unexpected homing patterns of tumor associated antigen (TAA) specific T cells, depending on the mode of T cell administration, which subsequently determined the treatment efficiency of solid tumors. In the next step, we will elucidate the homing kinetics and mode and sites of action of therapeutic TAA specific T cells in T cell-based immunotherapy of cancer.

 

 

 

  • In project B07, Klaus Schulze-Osthoff analyzes the role of two novel NFκB inhibitor proteins, IκBNS and IκBζ, in macrophages, in particular with regard to macrophage polarization and their role in inflammation. This should not only lead to the identification of new target genes of NFκB but may also open up new therapeutic possibilities for the selective modulation of distinct subsets of such genes.

 

 

 

  • In project B08, Leticia Quintanilla-Martinez de Fend and Falko Fend analyze the transcription factor C/EBPβ (CCAAT/enhancer binding protein beta) that is specifically overexpressed in ALK+ anaplastic large cell lymphoma (ALCL), and a central target of ALK-mediated oncogenesis. During the next period, we want to analyze selected candidate genes that are probably essential for ALK-mediated oncogenesis, among them the RNA helicase DDX21(RHII/Guα), which is differentially expressed in ALK+ vs. ALK- ALCL. DDX21 interacts with AP1 transcription factor proteins, and also plays an important role in pre-rRNA processing and ribosomal biogenesis of ALK+ ALCL cells. We also plan to investigate miRNA expression patterns and their regulation with a variety of strategies in both ALK+ and ALK- cell lines, and transfected T cells. Candidate miRNAs and genes will be validated in primary tumors, and similarities and differences in oncogenic pathways between ALK+ and ALK- ALCL will be investigated.

 

 

 

  • Project B09 is a project in area B in which the principal investigators are promising young scientists. Kamran Ghoreschi arrived from the NIH, where he carried out excellent work on Th17 biology that was published in Nature and Nature Immunology. Amir Yazdi joined us after a research fellowship in the Department of the late Jürg Tschopp at the University of Lausanne, where he had undertaken seminal work on the inflammasome that was published in Immunity and Nature. These two PIs now jointly lead project B09 on the cross-regulation of cytokines in Th2-mediated disease using a mouse model. First, this group will investigate the impact of IL-4 and its downstream signaling protein STAT6 on the expression and cleavage of IL-1β and IL-33 in macrophages, dendritic cells and keratinocytes. Second, IL-1R and ST2 expression and signaling as well as the induction of their naturally occurring inhibitors will be studied in the context of Th2 cytokines. Balancing the immune response by IL-4, IL-1β and IL-33 will help to understand the pathogenesis of skin inflammation and to establish the molecular basis for new immunotherapies.

 

 

 
 
 
 

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