SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8⁺ T cell responses

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Viral mutations can lead to immune escape from T cells.
• The role of mutations in regions flanking SARS-CoV-2 epitopes is largely unknown.

Purpose of the Study:

• To investigate how mutations in flanking regions of SARS-CoV-2 nucleoprotein CD8+ T cell epitopes affect proteasomal processing and T cell activation.
• To understand the mechanisms of immune escape and potential enhancement mediated by these mutations.

Main Methods:

• Analysis of two SARS-CoV-2 nucleoprotein CD8+ T cell epitopes.
• Assessment of proteasomal processing efficiency for epitope production.
• Measurement of CD8+ T cell responses to mutated epitopes.

Main Results:

• The NP-Q7K mutation within an epitope region decreased T cell responses, suggesting immune escape due to impaired proteasomal processing.
• Flanking mutations (NP-P6L and NP-D103N/Y) enhanced CD8+ T cell responses by improving epitope production via the proteasome.
• Mutations outside the core epitope sequence significantly influence proteasomal processing.

Conclusions:

• SARS-CoV-2 mutations in flanking regions can modulate T cell immunity.
• These mutations can either promote immune escape or enhance T cell activation.
• Understanding these effects is crucial for designing effective vaccines against SARS-CoV-2.