Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies

• Published in: eLife 2024-05, Vol.12
• Main Authors: Lu, Xiuyuan, Hayashi, Hiroki, Ishikawa, Eri, Takeuchi, Yukiko, Dychiao, Julian Vincent Tabora, Nakagami, Hironori, Yamasaki, Sho
• Format: Article
• Language: English
• Subjects: Adult; Age groups; Antibodies; Antibodies, Viral - blood; Antibodies, Viral - immunology; antibody longevity; Antigens; Blood & organ donations; BNT162 Vaccine - administration & dosage; BNT162 Vaccine - immunology; CD4 antigen; clonotypic tracing; COVID-19; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 vaccines; COVID-19 Vaccines - administration & dosage; COVID-19 Vaccines - immunology; Epitopes; Epitopes, T-Lymphocyte - immunology; Female; Gene expression; Humans; Immunological memory; Immunology and Inflammation; Infections; Lymphocytes; Lymphocytes T; Male; Middle Aged; mRNA vaccines; Ribonucleic acid; RNA; SARS-CoV-2; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - immunology; T cell receptors; T cell response; T-Lymphocytes, Helper-Inducer - immunology; Tfh cells; Vaccination; vaccine
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.89999

SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as 'sustainers'), but not in 'decliners'. Even before vaccination, S-reactive CD4 T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.