CD8⁺ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal...

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Understanding T-cell immunity to SARS-CoV-2 is crucial for managing the COVID-19 pandemic.
• Cross-recognition with seasonal coronaviruses may influence T-cell responses to SARS-CoV-2.

Purpose of the Study:

• To investigate the immunodominant T-cell response to SARS-CoV-2 nucleocapsid (N) protein.
• To determine the basis of T-cell cross-reactivity between SARS-CoV-2 and seasonal coronaviruses.

Main Methods:

• Screening of SARS-CoV-2 peptide pools in COVID-19-recovered individuals and unexposed donors.
• In vitro peptide stimulation, crystal structure analysis, and T-cell receptor sequencing.
• Analysis of T-cell responses to conserved epitopes across different coronavirus strains.

Main Results:

• The SARS-CoV-2 nucleocapsid (N) protein induced an immunodominant T-cell response in HLA-B7+ individuals, also seen in unexposed donors.
• A conserved N-protein epitope drove cross-reactivity with OC43 and HKU-1 betacoronaviruses, but not 229E or NL63 alphacoronaviruses.
• T-cell cross-reactivity was mediated by specific T-cell receptor repertoires (TRBV27 bias, long CDR3β loop) and influenced by peptide conformation.

Conclusions:

• Identified a specific SARS-CoV-2 epitope responsible for cross-reactive T-cell immunity with seasonal coronaviruses.
• Structural differences in viral epitopes explain selective cross-reactivity.
• Findings suggest a mechanism for potentially long-lasting protective T-cell immunity against SARS-CoV-2 and related coronaviruses.