The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein

Precise elucidation of the antigen sequences for T cell immunosurveillance greatly enhances our ability to understand and modulate humoral responses to viral infection or active immunization. Mass spectrometry is used to identify 526 unique sequences from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein extracellular domain in a complex with human leukocyte antigen class II molecules on antigen-presenting cells from a panel of healthy donors selected to represent a majority of allele usage from this highly polymorphic molecule. The identified sequences span the entire spike protein, and several sequences are isolated from a majority of the sampled donors, indicating promiscuous binding. Importantly, many peptides derived from the receptor binding domain used for cell entry are identified. This work represents a precise and comprehensive immunopeptidomic investigation with the SARS-CoV-2 spike glycoprotein and allows detailed analysis of features that may aid vaccine development to end the current coronavirus disease 2019 (COVID-19) pandemic. [Display omitted] •Dendritic cells display peptides spanning the entire SARS-CoV-2 spike protein•HLA-II peptides from 11 regions are presented by a majority of the analyzed donors•One region with promiscuous HLA-II presentation is conserved with SARS-CoV•The correlation of presented to predicted peptides is low Knierman et al. pulse dendritic cells derived from healthy human donors with the SARS-CoV-2 spike glycoprotein to determine the precise sequences presented for T cell surveillance. Regions with promiscuous presentation are identified, with poor correlation to predicted epitopes. One region with promiscuous presentation is conserved with the SARS-CoV spike glycoprotein sequence.