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Cell. 2019 Aug 8;178(4):1016-1028.e13. doi: 10.1016/j.cell.2019.07.009.

T-Scan: A Genome-wide Method for the Systematic Discovery of T Cell Epitopes.

Author information

1
Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard University Medical School, Boston, MA, USA.
2
Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard University Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
3
Departments of Surgery and Pathology, Duke University Medical Center, 571 Research Drive, Suite 433, Box 2606, Durham, NC 27710, USA.
4
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Department of Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
5
Departments of Surgery, Immunology, and Pathology, Duke University Medical Center, 571 Research Drive, Suite 433, Box 2606, Durham, NC 27710, USA.
6
Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard University Medical School, Boston, MA, USA. Electronic address: selledge@genetics.med.harvard.edu.

Abstract

T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules. Target cells functionally recognized by T cells are isolated using a reporter for granzyme B activity, and the antigens mediating recognition are identified by next-generation sequencing. We show T-Scan correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. We apply T-Scan to discover new viral antigens, perform high-resolution mapping of TCR specificity, and characterize the reactivity of a tumor-derived TCR. T-Scan is a powerful approach for studying T cell responses.

KEYWORDS:

T cell epitope; T cell screening; TCR epitope; TCR-specificity; antigen discovery; epitope discovery; epitope mutagenesis; epitope screening; immunological screening; off-target screening; peptide MHC recognition

PMID:
31398327
DOI:
10.1016/j.cell.2019.07.009

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