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

Summary The precise elucidation of the antigen sequences for T-cell immunosurveillance greatly enhances our ability to both understand and modulate humoral responses to viral infection or active immunization. Mass spectrometry is used to identify 526 unique sequences from 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 donors sampled 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 SARS-CoV-2 spike glycoprotein and allows detailed analysis of features which may aid vaccine development to end the current COVID-19 pandemic.