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Empty peptide-receptive MHC class I molecules for efficient detection of antigen-specific T cells

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  • Sunil Kumar Saini
  • Tripti Tamhane
  • Raghavendra Anjanappa
  • Ankur Saikia
  • Sofie Ramskov
  • Marco Donia
  • Inge Marie Svane
  • Søren Nyboe Jakobsen
  • Maria Garcia-Alai
  • Martin Zacharias
  • Rob Meijers
  • Sebastian Springer
  • Sine Reker Hadrup
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The peptide-dependent stability of MHC class I molecules poses a substantial challenge for their use in peptide-MHC multimer-based approaches to comprehensively analyze T cell immunity. To overcome this challenge, we demonstrate the use of functionally empty MHC class I molecules stabilized by a disulfide bond to link the α1 and α2 helices close to the F pocket. Peptide-loaded disulfide-stabilized HLA-A*02:01 shows complete structural overlap with wild-type HLA-A*02:01. Peptide-MHC multimers prepared using disulfide-stabilized HLA-A*02:01, HLA-A*24:02, and H-2Kb can be used to identify antigen-specific T cells, and they provide a better staining index for antigen-specific T cell detection compared with multimers prepared with wild-type MHC class I molecules. Disulfide-stabilized MHC class I molecules can be loaded with peptide in the multimerized form without affecting their capacity to stain T cells. We demonstrate the value of empty-loadable tetramers that are converted to antigen-specific tetramers by a single-step peptide addition through their use to identify T cells specific for mutation-derived neoantigens and other cancer-associated antigens in human melanoma.

Original languageEnglish
JournalNature Immunology
Volume4
Issue number37
ISSN1529-2908
DOIs
Publication statusPublished - 19 Jul 2019

ID: 57727789