Regulatory T Cells May Influence Severity of COVID-19 Among Sexes


Link between male or female sex and the severity of COVID-19 may be found in a subset of regulatory T cells.

Circulating follicular regulatory T cells (cTfr)—a subset of regulatory T cells (Tregs)—and other Treg subsets may explain the link between sex and severity of COVID-19, according to a recent study published in PNAS. Tregs were found to proliferate in the T cells of critically ill patients, according to the investigators.

“Patients with COVID-19 have a reduced ratio of cTfr to a network of antibody production-associated cells such as T-peripheral helper (Tph), plasma blasts, and CD11c+CXCR5− extrafollicular/atypical B cells, which in turn is strongly correlated with neutralizing antibody levels in the serum,” the study authors wrote in the paper.

Current understanding of the differences in antibody production between the male and female sexes during COVID-19 is murky, according to the investigators. Previous research associated the female sex with a greater antibody response and susceptibility to autoimmune diseases, but antibody levels and disease susceptibility in COVID-19 appears to be higher for males, according to the study.

The effects are Tfr control plasma cell formation, antibody quality, B cell memory, and they protect the lungs against influenza. Tfr and Tregs may be important in understanding a person’s susceptibility and recovery from COVID-19.

“There is significant evidence that Tfr have an important role in suppressing plasma cell generation, controlling the specificity and memory of the antibody response to acute viral infections, and preventing autoreactive antibodies from developing in this same context,” the authors wrote.

Female patients had a higher proportion of B cells, as opposed to the higher ration of plasma cells and Ki67+CD38+ Tregs associated with male patients. There was a large association between the female sex and cTfr as well.

“Since a primary role of Tfr is the control of plasma cell formation, this suggested a causative link between the inverse relationship of Tfr and plasma cells/blasts among the sexes,” the study authors wrote.

cTfr and Tfh were found to contribute to the immunobiology of COVID-19. When a person had a decreased proportion of cTfr, they opposingly showed a higher amount of activated Tfh. Additionally, Tfr was linked inversely to plasma cells/blasts, especially in patients with severe COVID-19.

Despite the male sex as a risk factor for COVID-19 disease outcome, the recent data found that they have higher antibody (neutralizing and autoantibody) response compared to the female sex in that it was more active but dysregulated. In effect, patients of the male sex had more disrupted cTfr function. However, there were no significant differences in the proportion of plasma cells/blasts, cTfr and Tph Tregs between the 2 sexes.

“Treg subgroups were central parts of the top 5 most severity-associated…or sex-associated cellular populations in COVID-19,” the study authors wrote. “While further work is required to truly separate cause from effect, the reduction of cTfr in all COVID-19 patients, which is further exaggerated in male patients, may underly dysregulated antibody production driven by Tph and atypical B cell responses.”


Søndergaard J, Tulyeu J, Edahiro R, Wing J. A sex-biased imbalance between Tfr, Tph, and atypical B cells determines antibody responses in COVID-19 patients. PNAS. January 20, 2023.

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