Human precursor T follicular regulatory cells are primed for differentiation into mature Tfr and disrupted during severe infections

T follicular regulatory cells (Tfr) play a pivotal role in maintaining immune self-tolerance and prevention of autoantibody induction. However, the stages of Tfr formation have still not been clarified. Here, we found that 30 to 50% of circulating Tfr in human blood have a naïve-like phenotype (preTfr, CD45RA⁺CD45RO^-Foxp3⁺CXCR5⁺). PreTfr are expandable in vitro while retaining suppressive capacity. They are transcriptionally similar to naïve T_regs (nT_regs) ex vivo, but after stimulation, they gain increased expression of Tfr-related suppressive molecules such as IL-1RA, suggesting that they are primed for full differentiation into mature Tfr. Further, we demonstrate that preTfr but not nT_reg are significantly reduced in the blood of patients with COVID-19 and patients with sepsis and that this loss is correlated with increased anti-interferon-γ antibodies and activated atypical B cells. Together, these data suggest that Tfr are disrupted at the earliest stage of their formation during severe disease and may be an important therapeutic target in future vaccine developments.