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

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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.