FOR 2799:  Receiving and Translating Signals via the gamma-delta T Cell Receptor

• Subject Area: Medicine
• Term: since 2018
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 395236335

γδ T cells were discovered over 30 years ago. However, in contrast to their MHC-restricted αβ T cell counterparts, their place in cellular immunity of vertebrates is not yet defined. Over the past few years, the visibility and scientific output of the γδ T cell field has rapidly gained momentum due to outstanding new findings regarding the identification of potential ligands for the γδ TCR, insights into the role of γδ T cells in the control of infectious diseases, and due to the recognition of γδ T cells as a potential cellular therapy against tumors. Thus, γδ T cell research is a hot topic with a lot of potential for translation into clinical application. Notably, several German research groups have recently contributed important new findings to the γδ T cell field. Together, we are therefore confident that that it is the right time to join our forces within the frame of a DFG Research Unit. In this proposal, we hypothesize that recognition of cognate antigen via the γδ TCR leads to intracellular signal transduction and γδ T cell activation, differentiation and execution of effector functions, and activated γδ T cells proliferate and thereby focus the γδ T cell repertoire. The specific aims of this consortium are to cooperatively monitor and define how γδ T cells participate in immune responses against cancer and infections, to better understand how the γδ TCR is activated, and to investigate the consequences of γδ T cell activation. To this end, our portfolio ranges from clinical observational studies to the investigation of basic biochemical questions and from experimental in vivo studies back to translational clinical approaches. We will exchange and jointly apply our complementary experimental systems and further push forward novel technologies such as high-resolution TCR repertoire analysis, high-dimensional phenotypic analysis by multi-parameter and mass cytometry and single cell RNA sequencing to understand how the γδ TCR receives and transduces external signals. On the long run, the overarching goals of FOR 2799 will be i) to increase the visibility of German γδ T cell research, ii) to identify how γδ T cells respond to neoplastic and infected cells and iii) to explore how our knowledge on γδ T cell activation can be translated into clinical strategies for their in vivo manipulation, e.g. in anti-tumor therapy.

• DFG Programme: Research Units

Projects

• Adaptive immune responses of γδ T cells in murine cytomegalovirus infections (Applicant Winkler, Thomas )
• Chimeric γδ T Cell Receptors (Applicant Schamel, Wolfgang )
• Comparative investigation of the role of tumor-infiltrating and peripheral blood γδ T cells in melanoma rejection under checkpoint therapy (Applicant Wistuba-Hamprecht, Kilian )
• Coordination Funds (Applicant Prinz, Immo )
• Improving γδ T cell-based immunotherapy against cancer by studying signal initiation of the γδTCR (Applicant Minguet, Ph.D., Susana )
• Molecular control of γδ T cell development (Applicant Ravens, Sarina )
• Peripheral shaping of γδ TCR repertoires (Applicant Prinz, Immo )
• Phylogeny and species comparison as tools for understanding antigen recog-nition by human γδ T-cells (Applicant Herrmann, Thomas )
• Strategies to enhance cytotoxicity of tumor-infiltrating γδ T-cell subsets against autologous tumor cells (Applicant Wesch, Daniela )
• Structural characterization of γδ-TCR-ligand interaction (Applicant Krey, Thomas )

• Spokesperson: Professor Dr. Immo Prinz