Nobel Laureate-Led Research Uncovers Disruption of Immune Cell Precursors in Severe COVID-19 Cases

A groundbreaking study conducted by a collaborative team at the University of Osaka, including renowned Nobel Prize laureate Professor Shimon Sakaguchi, has shed light on the immune system's response during severe COVID-19 infections. The researchers identified a previously uncharacterized subset of immune cells known as precursor T follicular regulatory cells (preTfr), which play a vital role in preventing autoimmune responses by regulating antibody production.

Their research, published in Science Advances, reveals that levels of preTfr cells are significantly diminished in patients suffering from severe COVID-19 and sepsis. This loss correlates with an increase in harmful autoantibodies targeting interferon-gamma, contributing to immune dysregulation.

T follicular regulatory (Tfr) cells are specialized immune cells that control antibody synthesis. While circulating Tfr cells are known to exist in the blood, their development stages were not fully understood until now. The study discovered that a substantial portion of circulating Tfr are in a naive-like phase called preTfr, characterized by the expression of CD45RA and CXCR5 markers.

Further experiments demonstrated that preTfr cells could be expanded in laboratory settings while maintaining their immune-suppressive abilities. Upon stimulation, they exhibited increased expression of molecules like IL-1RA, indicating their readiness to differentiate into mature Tfr cells. Interestingly, preTfr cells also displayed enhanced capacities for wound healing.

In blood samples taken from patients with severe COVID-19, bacterial sepsis, and healthy controls, the researchers observed a marked reduction of both preTfr and mature Tfr cells in COVID-19 and sepsis cases. The stable levels of naive regulatory T cells suggested that preTfr have a unique response pattern during severe infections.

The decline of preTfr cells was linked with the emergence of anti-interferon-gamma autoantibodies in late-stage COVID-19, alongside an increase in atypical activated B cells. Notably, COVID-19 patients who received mRNA vaccination showed an increase in preTfr and Tfr levels, especially after multiple doses, highlighting that these cells are involved in well-regulated immune responses. Their loss during severe disease may lead to immune dysregulation and the development of autoantibodies.

"Our findings indicate that Tfr disruption begins early during severe infection,» states Dr. James B. Wing, the study's corresponding author. "Understanding the role of preTfr cells could open avenues for new therapeutic strategies to prevent autoantibody production and improve vaccine responses."

This research emphasizes the importance of preserving immune regulation during infections and provides insights into autoimmune complications observed in severe COVID-19 cases. The discovery of preTfr as a distinct immune cell subset may pave the way for innovative treatments targeting autoimmune responses in infectious and autoimmune diseases.

For more details, see the full study published in Science Advances: link.

Source: https://medicalxpress.com/news/2025-10-team-nobel-prize-laureate-reveals.html