Human naïve-like T follicular regulatory cells are primed for differentiation into mature Tfr and disrupted during severe infections.

Regulatory T cells (Tregs) play a pivotal role in maintaining immune self-tolerance and homeostasis. T Follicular regulatory cells (Tfr) are a specific Treg population expressing the chemokine receptor CXCR5 and is known to regulate antibody production and prevent autoantibody induction. However, the stages of Tfr formation have still not been clarified. Here we found that 30-50% of Tfr in human blood have a naïve-like phenotype (nTfr, CD45RA+CD45RO−Foxp3+CXCR5+). nTfr are expandable in vitro while retaining suppressive capacity. nTfr are transcriptionally similar to nTreg ex-vivo but after stimulation, they gain increased expression of Tfr-related suppressive molecules such as IL1RA, suggesting they are primed for full differentiation into mature Tfr. We also found that nTfr has enhanced wound healing capacity, indicating a non-canonical function of this Treg subset. Further, we demonstrate that nTfr but not nTreg are significantly reduced in the blood of COVID-19 and sepsis patients and that this loss is correlated with increased anti-Interferon-γ antibodies. 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.