Polyfunctional T peripheral helper cells are associated with the magnitude and durability of antibody responses after COVID‐19

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Objective 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. Methods 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. Results 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. Conclusion 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.