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

[tetano]

Cell


. 2021 Jun 3;S0092-8674(21)00701-7.
doi: 10.1016/j.cell.2021.05.046. Online ahead of print.
Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs


Shira Weingarten-Gabbay ¹ , Susan Klaeger ² , Siranush Sarkizova ³ , Leah R Pearlman ³ , Da-Yuan Chen ⁴ , Kathleen M E Gallagher ⁵ , Matthew R Bauer ⁶ , Hannah B Taylor ³ , W Augustine Dunn ⁷ , Christina Tarr ⁷ , John Sidney ⁸ , Suzanna Rachimi ³ , Hasahn L Conway ⁴ , Katelin Katsis ⁹ , Yuntong Wang ⁷ , Del Leistritz-Edwards ⁷ , Melissa R Durkin ⁷ , Christopher H Tomkins-Tinch ¹⁰ , Yaara Finkel ¹¹ , Aharon Nachshon ¹¹ , Matteo Gentili ³ , Keith D Rivera ³ , Isabel P Carulli ¹² , Vipheaviny A Chea ¹² , Abishek Chandrashekar ¹³ , Cansu Cimen Bozkus ¹⁴ , Mary Carrington ¹⁵ , MGH COVID-19 Collection & Processing Team; Nina Bhardwaj ¹⁴ , Dan H Barouch ¹⁶ , Alessandro Sette ¹⁷ , Marcela V Maus ¹⁸ , Charles M Rice ¹⁹ , Karl R Clauser ³ , Derin B Keskin ²⁰ , Daniel C Pregibon ⁷ , Nir Hacohen ²¹ , Steven A Carr ³ , Jennifer G Abelin ³ , Mohsan Saeed ²² , Pardis C Sabeti ²³



Collaborators, Affiliations

• PMID: 34171305
• DOI: 10.1016/j.cell.2021.05.046

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.

Keywords: HLA Class I; SARS-CoV-2; T Cell response; coronavirus; immunogenicity; out-of-frame ORF immunopeptidomics; viral infection.