The rat as new model for the analysis of iNKT cell antigen-recognition and function

iNKT细胞，也被称为I型NKT细胞，与病原体和肿瘤作斗争，抑制自身免疫性疾病，但它们也可以促进许多病理条件的发展。它们的标志是一种特征性t细胞抗原受体（iNKT-TCR）的表达，该受体识别（糖）脂质复合物和细胞表面分子CD1d。所有inkt - tcr都含有一个不变的α-链，其抗原结合位点由TCR-AV14基因和-AJ18基因编码。我们小组开发的新工具将首次允许直接分析大鼠体内的iNKT细胞。第一部分旨在更好地了解inkt - tcr抗原识别的机制。为此，将分析iNKT- tcr突变体和来自iNKT细胞亚群的tcr抗原结合，特别是大鼠AV14基因变异在多大程度上影响抗原识别。该项目的第二部分利用大鼠和人类iNKT细胞之间的相似性，建立大鼠作为iNKT细胞治疗应用的新模型。iNKT细胞将在体外扩增，并选择所需的功能，如生产某些细胞因子。随后，将这些iNKT细胞转移到免疫活性或辐照动物体内，研究iNKT细胞的命运和功能。

iNKT cells, also designated as type I NKT cells, fight against pathogens and tumors, and suppress autoimmune diseases but they can also promote development of numerous pathological conditions. Their hallmark is the expression of a characteristic type of T-cell antigen receptor (iNKT-TCR), which recognizes complexes of (glyco)lipids and the cell surface molecule CD1d. All iNKT-TCRs contain an invariant α-chain, whose antigen-binding site is encoded by the TCR-AV14 gene and the -AJ18 gene. New tools developed by our group will allow for the first time direct analysis of iNKT cells in the rat. The first part aims for a better understanding of the mechanisms of antigen-recognition by iNKT-TCRs. To this end iNKT-TCR mutants and TCRs from iNKT cell subpopulations will be analyzed for antigenbinding and specifically to which extent rat AV14 gene-variability may affect antigen-recognition. The second part of the project uses similarities between rat and human iNKT cells to establish the rat as new model for therapeutic applications of iNKT cells. iNKT cells will be expanded in vitro and selected for desired features such as production of certain cytokines. Subsequently, these iNKT cells will be transferred into immunocompetent or irradiated animals and fate and function of the iNKT cells will be studied.