Coordination Funds

与αβ-T细胞相比，γδ-T细胞在健康和疾病中的生物学知之甚少。我们知道γδ T细胞在脊椎动物中高度保守，并且它们在胎儿生命的早期就出现了。γδ T细胞表现出高度多样的T细胞受体（TCR）库，特别是关于它们的TCR δ链。然而，仍然不清楚TCR-配体相互作用如何控制胸腺选择过程和外周中γδ-TCR库的形成。这可能是因为目前还没有γδ-TCR如何被特异性抗原激活的总体概念，并且迄今为止已经鉴定出非常少的γδ-T细胞配体。在当前的资助期（从2018年10月至2021年9月的三年），我们已经建立了一个充满活力的网络，并正在分享协议，材料和问题，以调查信号如何在γδ TCR中接收和翻译。尽管SARS-Cov-2大流行迫使我们的研究实验室于2020年初部分关闭至少三个月，但我们合作建立了一个真正互动的DFG研究小组。FOR 2799已经有了国际知名的科学成果，我们正在追求一个雄心勃勃的计划，以传播我们的研究成果和问题，尽管这些非常时期，这次更新申请的主要目标是进一步加入我们的集体力量，探索γδ TCR如何工作，以及如何将这些知识用于免疫治疗，并潜在地作为一种新的工具来对抗传染病。为此，我们定义了三个主要合作轴：1）我们将使用实验模型和临床观察来分析γδ TCR在免疫应答期间γδ T细胞活化中的作用。2）我们将使用基于CRISPR/Cas9 sgRNA的筛选测定，并鉴定γδ TCR的新型配体，并使用结构分析来表征其γδ TCR活化模式。3）我们将联合收割机一系列药理学和生物化学方法来操纵γδ TCR及其信号转导机制，以改善和优化γδ T细胞和γδ TCR构建体用于癌症免疫治疗的功效。从中长期的角度来看，该研究小组的发现应该强烈支持在免疫治疗中使用γδ TCR和γδ汽车的转化方法。

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.