byUniversity of Osaka

Loss of preTfr during COVID-19 correlates with autoantibody production. A) preTfr cells differentiate into mature Tfr cells, which secrete IL-1RA to suppress plasma cell formation and antibody production. B) During severe COVID-19 infection, preTfr cell frequencies decline over time (red line), while anti-cytokine autoantibody levels increase (green line), suggesting loss of preTfr contributes to dysregulated autoantibody production. Credit:Science Advances(2025). DOI: 10.1126/sciadv.adv6939

A research team at The University of Osaka, joined by Professor Shimon Sakaguchi—the latest Nobel Laureate in Physiology or Medicine—has identified a previously uncharacterized subset of immune cells called precursor T follicular regulatory cells (preTfr) that play a critical role in preventing autoantibody production.

Their article, "Human precursor T follicular regulatory cells are primed for differentiation into mature Tfr and disrupted during severe infections," ispublishedinScience Advances.

The study reveals that these cells are significantly reduced in patients with severe COVID-19 and sepsis, and their loss correlates with increased levels of harmful autoantibodies against interferon-gamma.

T follicular regulatory (Tfr) cells are specializedimmune cellsthat control antibody production. While researchers knew that circulating Tfr existed in the blood, the stages of their development remained unclear. This study demonstrates that a significant proportion of circulating Tfr have a naive-like phenotype called preTfr, characterized by CD45RA and CXCR5 expression.

The research team found that preTfr cells are expandable in laboratory conditions while retaining immune-suppressive capacity. When stimulated, these cells increase expression of suppressive molecules such as IL-1RA, suggesting they are primed for differentiation into mature Tfr. The study also revealed that preTfr possess enhanced wound healing capacity.

Inblood samplesfrom patients with severe COVID-19, bacterial sepsis, and healthy controls, both preTfr and mature Tfr were significantly reduced in COVID-19 and sepsis. Conventional naive regulatory T cells remained stable, indicating preTfr have a distinct response pattern during severe infections.

The reduction in preTfr correlated with increased anti-interferon-gamma autoantibodies in late COVID-19. Patients with these autoantibodies also showed increased activated atypical B cells.

Unlike severeinfection, SARS-CoV-2 mRNA vaccination increased both preTfr and mature Tfr frequency, particularly after later doses, suggesting preTfr participate in well-regulated immune responses but their loss during severe infection causes dysregulation and autoimmune antibody production.

"These data suggest that Tfr are disrupted at the earliest stage of their formation during severe disease," says Dr. James B. Wing, corresponding author.

"The discovery of preTfr as a distinct immune subset has important implications for understanding why some patients develop autoantibodies during severe infections and may provide new therapeutic targets for future vaccine developments and treatments for autoimmune diseases."

More information: Janyerkye Tulyeu et al, Human precursor T follicular regulatory cells are primed for differentiation into mature Tfr and disrupted during severe infections, Science Advances (2025). DOI: 10.1126/sciadv.adv6939 Journal information: Science Advances

Provided by University of Osaka