Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs.

Abstract

T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.

• Authors: Shira Weingarten-Gabbay, Susan Klaeger, Siranush Sarkizova, Leah R Pearlman, Da-Yuan Chen, Kathleen M E Gallagher, Matthew R Bauer, Hannah B Taylor, W Augustine Dunn, Christina Tarr, John Sidney, Suzanna Rachimi, Hasahn L Conway, Katelin Katsis, Yuntong Wang, Del Leistritz-Edwards, Melissa R Durkin, Christopher H Tomkins-Tinch, Yaara Finkel, Aharon Nachshon, Matteo Gentili, Keith D Rivera, Isabel P Carulli, Vipheaviny A Chea, Abishek Chandrashekar, Cansu Cimen Bozkus, Mary Carrington, MGH COVID-19 Collection & Processing Team, Nina Bhardwaj, Dan H Barouch, Alessandro Sette, Marcela V Maus, Charles M Rice, Karl R Clauser, Derin B Keskin, Daniel C Pregibon, Nir Hacohen, Steven A Carr, Jennifer G Abelin, Mohsan Saeed, Pardis C Sabeti
• Journal: Cell (Cell) Vol. 184 Issue 15 Pg. 3962-3980.e17 (07 22 2021) ISSN: 1097-4172 [Electronic] United States
• PMID: 34171305 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Epitopes, T-Lymphocyte
• Histocompatibility Antigens Class I
• Peptides
• Proteome

Topics

• A549 Cells
• Alleles
• Amino Acid Sequence
• Animals
• Antigen Presentation (immunology)
• COVID-19 (immunology, virology)
• Epitopes, T-Lymphocyte (immunology)
• Female
• HEK293 Cells
• Histocompatibility Antigens Class I (immunology)
• Humans
• Kinetics
• Male
• Mice
• Open Reading Frames (genetics)
• Peptides (chemistry, immunology)
• Proteome (immunology)
• SARS-CoV-2 (immunology)
• T-Lymphocytes (immunology)