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Nat Biotechnol. 2018 Nov 19. doi: 10.1038/nbt.4303. [Epub ahead of print]

T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide-MHC complexes.

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Department of Micro and Nanotechnology, Technical University of Denmark, Lyngby, Denmark.
Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark.
Department of Medicine, Divisions of Dermatology, University of Washington, Seattle, Washington, USA.
Department of Medicine, University of Washington, Seattle, Washington, USA.
Division of Vaccine and Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Translational Skin Cancer Research, University Hospital Essen and University of Duisburg-Essen, Essen, Germany.
Department of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Buenos Aires, Argentina.


The promiscuous nature of T-cell receptors (TCRs) allows T cells to recognize a large variety of pathogens, but makes it challenging to understand and control T-cell recognition. Existing technologies provide limited information about the key requirements for T-cell recognition and the ability of TCRs to cross-recognize structurally related elements. Here we present a 'one-pot' strategy for determining the interactions that govern TCR recognition of peptide-major histocompatibility complex (pMHC). We measured the relative affinities of TCRs to libraries of barcoded peptide-MHC variants and applied this knowledge to understand the recognition motif, here termed the TCR fingerprint. The TCR fingerprints of 16 different TCRs were identified and used to predict and validate cross-recognized peptides from the human proteome. The identified fingerprints differed among TCRs recognizing the same epitope, demonstrating the value of this strategy for understanding T-cell interactions and assessing potential cross-recognition before selection of TCRs for clinical development.


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