Coordination Funds

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Compared with αβ-T cells, the biology of γδ-T cells in health and disease is poorly understood. We know that γδ T cells are highly conserved among vertebrates and that they arise very early in fetal life. γδ T cells exhibit a highly diverse T cell receptor (TCR) repertoire, particularly with respect to their TCR δ-chains. However, it is still not clear how TCR-ligand interactions control thymic selection processes and the formation of the γδ-TCR repertoire in the periphery. This may be because there is currently no overarching concept of how γδ-TCRs are activated by specific antigen and very few γδ-T cell ligands have been identified to date. In the current funding period (three years from 10/2018 - 09/2021), we have established a vibrant network and are sharing protocols, materials, and questions to investigate how signals are received and translated across the γδ TCR. Although the SARS-Cov-2 pandemic forced a partial closure of our research labs for at least three months in early 2020, we have cooperatively built a truly interactive DFG research group. Already, FOR 2799 has an internationally visible scientific output and we are pursuing an ambitious program to disseminate our research results and questions despite these extraordinary times.The main goal of this renewal application is to further join our collective forces to explore how the γδ TCR works and how this knowledge can be used in immunotherapy and potentially as a new tool against infectious diseases. To this end, we have defined three main axes of collaboration:1) We will use experimental models and clinical observations to analyze the role of the γδ TCR in the activation of γδ T cells during an immune response.2) We will use CRISPR/Cas9 sgRNA-based screening assays and to identify novel ligands of the γδ TCR and characterize their mode of γδ TCR activation using structural analyses.3) We will combine an arsenal of pharmacological and biochemical methods to manipulate the γδ TCR and its signal transduction machinery to improve and optimize the efficacy of γδ T cells and γδ TCR constructs for cancer immunotherapy. In a mid- to long-term perspective, the findings of this research group should strongly support translational approaches to the use of γδ TCRs and γδ CARs in immunotherapy.