Conformational bias in SARS-CoV-2 Spike CD4+ T-cell epitope dominance

Area of Science:

• Immunology
• Virology
• Proteomics

Background:

• Adaptive immunity to SARS-CoV-2 relies on epitope-specific T cells for long-term protection.
• CD4+ T-cell responses are influenced by antigen-presenting cell type, endocytosis, and antigen conformation.
• Limited research exists on how antigen exposure circumstances alter epitope dominance via the MHC class II pathway.

Purpose of the Study:

• To investigate how SARS-CoV-2 spike protein conformation affects CD4+ T-cell epitope dominance.
• To determine if exposure history (infection vs. vaccination) influences epitope dominance patterns.

Main Methods:

• Modeled SARS-CoV-2 spike processing using limited proteolysis of soluble spike trimer.
• Analyzed CD4+ T-cell epitope dominance by measuring IL-2 Elispot responses to peptides from stable and unstable spike regions.

Main Results:

• Protease-sensitive sites in the spike protein were located at domain boundaries and unstable regions.
• The ratio of T-cell responses to stable versus unstable peptide pools differentiated between infection and vaccination in human cohorts.

Conclusions:

• Spike protein structure limits proteolysis, influencing epitope generation.
• Epitope dominance patterns can serve as biomarkers for SARS-CoV-2 exposure history and immune imprinting.
• Understanding these patterns may predict the protective capacity of CD4+ T-cell responses.