SARS-CoV-2 spike-specific T_FH cells exhibit unique responses in infected and vaccinated individuals

Long-term humoral immunity to SARS-CoV-2 is essential for preventing reinfection. The production of neutralizing antibody (nAb) and B cell differentiation are tightly regulated by T follicular help (T_FH) cells. However, the longevity and functional role of T_FH cell subsets in COVID-19 convalescents and vaccine recipients remain poorly defined. Here, we show that SARS-CoV-2 infection and inactivated vaccine elicited both spike-specific CXCR3⁺ T_FH cell and CXCR3^- T_FH cell responses, which showed distinct response patterns. Spike-specific CXCR3⁺ T_FH cells exhibit a dominant and more durable response than CXCR3^- T_FH cells that positively correlated with antibody responses. A third booster dose preferentially expands the spike-specific CXCR3⁺ T_FH cell subset induced by two doses of inactivated vaccine, contributing to antibody maturation and potency. Functionally, spike-specific CXCR3⁺ T_FH cells have a greater ability to induce spike-specific antibody secreting cells (ASCs) differentiation compared to spike-specific CXCR3^- T_FH cells. In conclusion, the persistent and functional role of spike-specific CXCR3⁺ T_FH cells following SARS-CoV-2 infection and vaccination may play an important role in antibody maintenance and recall response, thereby conferring long-term protection. The findings from this study will inform the development of SARS-CoV-2 vaccines aiming to induce long-term protective immune memory.