T cell antigen discovery via trogocytosis

• Published in: Nature methods Vol. 16; no. 2; pp. 183 - 190
• Main Authors: Li, Guideng, Bethune, Michael T., Wong, Stephanie, Joglekar, Alok V., Leonard, Michael T., Wang, Jessica K., Kim, Jocelyn T., Cheng, Donghui, Peng, Songming, Zaretsky, Jesse M., Su, Yapeng, Luo, Yicheng, Heath, James R., Ribas, Antoni, Witte, Owen N., Baltimore, David
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2019; Nature Publishing Group
• Subjects: 631/1647/664; 631/250/21; 631/250/2152; Adaptive Immunity; Analysis; Animals; Antigen-presenting cells; Antigens; Antigens - chemistry; B cells; Bioinformatics; Biological Microscopy; Biological Techniques; Biological transport; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biotinylation; Cell membranes; DNA - analysis; Epitopes - chemistry; Gene Library; Genetic Techniques; HEK293 Cells; Humans; Immune response; Immunology; Immunotherapy; Jurkat Cells; K562 Cells; Life Sciences; Ligands; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical schools; Membrane proteins; Methods; Mice; Neoantigens; Peptides; Peptides - chemistry; Phagocytosis; Plasma membranes; Proteins; Proteomics; Receptors, Antigen, T-Cell - chemistry; T cell antigen receptors; T cell receptors; T cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Tumor antigens; Tumors; United States
• ISSN: 1548-7091; 1548-7105; 1548-7105
• DOI: 10.1038/s41592-018-0305-7

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. Trogocytosis, the uptake of membrane proteins by an antigen-presenting cell from its cognate T cell, allows the identification of neoepitopes targeted by T cell receptors with high sensitivity.