Polyfunctional T peripheral helper cells are associated with the magnitude and durability of antibody responses after...

Examine the role of T cells in shaping and sustaining humoral immunity to SARS-CoV-2 and identify immune factors associated with durable antibody responses.

Unvaccinated adults (n = 67) with SARS-CoV-2 infection (Wuhan) of any severity were followed longitudinally for up to 14 months. Anti-Spike (S) binding and neutralising antibodies were measured. Bulk T cell IFNγ and IL-2 responses were assessed by Fluorospot to multiple viral proteins. S-specific T-cell subsets and functions were analysed in detail by flow cytometry in a subset of participants (n = 14), combining activation-induced markers (AIMs) and cytokines. Correlations between S-specific T-cell subsets, their polyfunctionality and antibody levels over time were defined.

Over 14 months post infection, anti-S IgG and neutralising antibodies declined significantly but remained detectable in > 85% of participants. Bulk T-cell IFNγ and IL-2 responses persisted without significant reduction. However, S-specific CD4 T cells declined over time. A large proportion of these were peripheral helper T cells (Tph; CXCR5^-PD-1⁺), which were the main producers of IL-21 and showed marked polyfunctionality during early convalescence, in contrast to circulating follicular helper T cells (cTfh). The early presence of polyfunctional, IL-21-producing Tph strongly correlated with S-specific IgG and neutralising antibodies early post-infection and predicted neutralising antibody maintenance a year later. Older age correlated with higher Tph and antibody levels.

Early S-specific T-cell responses-particularly polyfunctional, IL-21-producing Tph cells-play a key role in sustaining durable antibody levels post-infection, offering insights for future vaccine strategies and understanding long-term immunity.