Functional analysis of the adhesion receptor CD155 and its ligands

CD155是免疫球蛋白超家族的一种粘附受体。CD155在内皮细胞或上皮细胞上表达，通过与连接蛋白-3络合，有助于粘附连接的建立。然而，CD155也在多种造血细胞如树突状细胞、NK细胞和T细胞上表达。在过去和现在的资助期内，我们成功地证明了CD155在免疫系统中的作用，我们自己和其他人的结果表明，CD155与CD96、CD226或TIGIT的结合对于完成免疫相关任务至关重要。在接下来的资助期内，我们希望重点研究CD155及其配体在调节性T细胞（Treg）和CD8 T效应细胞的生物活性中的功能，这是迄今为止研究中被忽视的主题。在我们的研究计划中，我们将包括在我们实验室建立的单克隆抗体，并中和每个配体与CD155的结合。此外，缺乏CD155、CD226或TIGIT的小鼠也可以从我们自己的育种中获得。还打算建立骨髓嵌合动物，为实验提供转基因T细胞。为此，CD155缺陷骨髓将被逆转录转导以表达野生型CD155或其突变体。这将有助于阐明CD155功能的分子基础。经典的体外方法将与体内实验相结合，探讨CD155及其配体在CD4和CD8 T细胞增殖中的作用，以及假设的Treg对T细胞增殖和功能的调节能力的影响。我们将利用移植物抗宿主病（GVHD）和抗原诱导关节炎的体内模型来研究CD155及其配体在疾病中的作用。探索这种受体/配体系统在诱导Treg的产生和功能中的假设贡献也将是有趣的。为了明确CD155及其配体对CD8 T细胞功能的影响，我们将利用基于ip -卵细胞小鼠的糖尿病模型，并利用CD8 OTI细胞和表达卵白蛋白表面结合版本的肿瘤细胞系EG7建立肿瘤模型。肿瘤细胞将被包括在表达野生型或突变型CD155的工程中，以解决CD155驱动的相互作用在肿瘤清除中的重要性和分子基础。

CD155 represents an adhesion receptor of the immunoglobulin superfamily. Expressed on endothelial or epithelial cells, CD155 contributes to the establishment of adherens junctions by complexing to nectin-3. However, CD155 is also expressed on a variety of hematopoietic cells such as dendritic cells, NK cells and T cells. In the past and present funding period we succeeded to demonstrate roles of CD155 in the immune system and our own results as well as that of others suggest that binding of CD155 to the ligands CD96, CD226 or TIGIT are of primordial importance to accomplish immune relevant tasks. In the coming funding period we wish to focus on the function of CD155 and its ligands in the biological activities of regulatory T cells (Treg) and CD8 T effector cells, a subject that has been neglected in research so far. In our research plans, we will include monoclonal antibodies established in our lab and neutralizing the binding of each of the ligands to CD155. Moreover, mice deficient for CD155, CD226 or TIGIT are available from our own breeding. It is also intended to establish bone marrow chimeric animals providing genetically modified T cells for the experiments. To this end, CD155 deficient bon marrow will be transduced retrovirally to express either wild type CD155 or mutants thereof. This will help elucidating the molecular basis of CD155 functions. Classical in vitro approaches will be combined with in vivo experiments to explore the contribution of CD155 and its ligands in proliferation of CD4 and CD8 T cells as well as the assumed influence on the modulatory capacity of Treg on T cell proliferation and function. We will make use of in vivo models of graft-versus-host-disease (GVHD) and antigen induced arthritis to study the role of CD155 and its ligand in the context of disease. It will also be of interest to explore a putative contribution of this receptor/ligand-system in the generation and function of induced Treg. To specifically address the impact of CD155 and its ligands on CD8 T cell function, we will utilize a diabetes model based on RIP-ova mice and establish a tumour model making use of CD8 OTI cells and the tumour cell line EG7 expressing a surface bound version of ovalbumin. Tumour cells will be included that were engineered to express wild type or mutant CD155 to address the importance and molecular basis of CD155 driven interactions in tumour clearance.