A sex-biased imbalance between Tfr, Tph, and atypical B cells determines antibody responses in COVID-19 patients

Sex-biased humoral immune responses to COVID-19 patients have been observed, but the cellular basis for this is not understood. Using single-cell proteomics by mass cytom-etry, we find disrupted regulation of humoral immunity in COVID-19 patients, with a sex-biased loss of circulating follicular regulatory T cells (cTfr) at a significantly greater rate in male patients. In addition, a male sex-associated cellular network of T-peripheral helper, plasma blasts, proliferating and extrafollicular/atypical CD11c+ memory B cells was strongly positively correlated with neutralizing antibody concentrations and nega-tively correlated with cTfr frequency. These results suggest that sex-specific differences to the balance of cTfr and a network of extrafollicular antibody production-associated cell types may be a key factor in the altered humoral immune responses between male and female COVID-19 patients.

Automated summary

Sex-specific differences in humoral immune responses to COVID-19 have been observed, with a higher loss of circulating follicular regulatory T cells (cTfr) in male patients. A network of cell types associated with extrafollicular antibody production is stronger in males and positively correlated with neutralizing antibody concentrations, while negatively correlated with cTfr frequency. These findings suggest that the balance of cTfr and the network of antibody-producing cell types may be a key factor in the altered humoral immune responses between male and female COVID-19 patients.