Official websites use. Share sensitive information only on official, secure websites. Correspondence and requests for materials should be addressed to G. T cell receptor TCR ligand discovery is essential for understanding and manipulating immune responses to tumors.
We developed a cell-based selection platform for TCR ligand discovery that exploits a membrane transfer phenomenon called trogocytosis. We discovered that T cell membrane proteins are transferred specifically to target cells that present cognate peptide-major histocompatibility complex MHC molecules.
Co-incubation of T cells expressing an orphan TCR with target cells collectively presenting a library of peptide-MHCs led to specific labeling of cognate target cells, enabling isolation of these target cells and sequencing of the cognate TCR ligand. We validated this method for two clinically employed TCRs and further used the platform to identify the cognate neoepitope for a subject-derived neoantigen-specific TCR. Thus, target cell trogocytosis is a robust tool for TCR ligand discovery that will be useful for studying basic tumor immunology and identifying new targets for immunotherapy.
Further information on research design is available in the Nature Research Reporting Summary linked to this article. T cells mediate adaptive immunity through direct, antigen-specific contact with target cells. The antigenic specificity of each T cell is determined by its unique TCR 1 , which binds a cognate peptide ligand epitope presented on MHC protein molecules on the target cell surface.
TCR ligand discovery is fundamental to characterizing adaptive immune responses to pathogens and tumors, as well as inappropriate responses to self- and dietary antigens 2 , 3.
