The HLA-II immunopeptidome of SARS-CoV-2

• Published in: Cell reports (Cambridge) Vol. 43; no. 1; p. 113596
• Main Authors: Weingarten-Gabbay, Shira, Chen, Da-Yuan, Sarkizova, Siranush, Taylor, Hannah B., Gentili, Matteo, Hernandez, Gabrielle M., Pearlman, Leah R., Bauer, Matthew R., Rice, Charles M., Clauser, Karl R., Hacohen, Nir, Carr, Steven A., Abelin, Jennifer G., Saeed, Mohsan, Sabeti, Pardis C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2024; Elsevier
• Subjects: antigen processing and presentation; CD4+ T cell; CP: Immunology; CP: Microbiology; HLA-II; immunity; immunopeptidome; noncanonical protein; SARS-CoV-2; viral antigen; CP: Immunology; SARS-CoV-2; CD4+ T cell; noncanonical protein; CP: Microbiology; immunopeptidome; HLA-II; antigen processing and presentation; immunity; viral antigen; CD4(+) T cell
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113596

Targeted synthetic vaccines have the potential to transform our response to viral outbreaks, yet the design of these vaccines requires a comprehensive knowledge of viral immunogens. Here, we report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides that are naturally processed and loaded onto human leukocyte antigen-II (HLA-II) complexes in infected cells. We identify over 500 unique viral peptides from canonical proteins as well as from overlapping internal open reading frames. Most HLA-II peptides colocalize with known CD4+ T cell epitopes in coronavirus disease 2019 patients, including 2 reported immunodominant regions in the SARS-CoV-2 membrane protein. Overall, our analyses show that HLA-I and HLA-II pathways target distinct viral proteins, with the structural proteins accounting for most of the HLA-II peptidome and nonstructural and noncanonical proteins accounting for the majority of the HLA-I peptidome. These findings highlight the need for a vaccine design that incorporates multiple viral elements harboring CD4+ and CD8+ T cell epitopes to maximize vaccine effectiveness. [Display omitted] •Immunopeptidome analysis of SARS-CoV-2 peptides naturally presented on HLA class II•Some HLA-II peptides originate from noncanonical SARS-CoV-2 proteins ORF9b and ORF3c•Class I and class II HLA complexes present different subsets of viral proteins Weingarten-Gabbay et al. map the repertoire of SARS-CoV-2 peptides naturally presented on HLA-II. The authors uncover HLA-II peptides originating from noncanonical ORFs and highlight striking differences between viral proteins that are presented on class I and class II HLAs, resulting in distinct targets for killer and helper T cells.