Pneumococcal transmission is driven by TNFR2+ regulatory T-cells

Background Pneumococcal serotype 1 (sequence type 217) is a leading cause of invasive disease outbreaks in Sub-Saharan Africa, causing significant morbidity and mortality. Understanding the transmission dynamics of hypervirulent strains such as ST217 is key to developing therapies and vaccines that can reduce outbreak incidence. Methods The transmission dynamics of ST217 were investigated using an adolescent mouse pneumococcal transmission model, representing the population mainly affected by disease outbreaks in Sub-Saharan Africa. Results We found that TNF receptor-2 (TNFR2)-positive regulatory T-cells (Tregs) paradoxically create the conditions that promote ST217 transmission. During ST217 colonisation, TNFR2 + Tregs accumulate in the nasopharynx and suppress IL-17A-producing γδT and Th17 cells, leading to reduced neutrophil-mediated pneumococcal clearance. This attenuated inflammatory response increases ST217 carriage density, consequently increasing nasal shedding to levels that increase transmission. Furthermore, we show that these TNFR2 + Treg responses are strain-dependent and driven by the pneumococcal toxin pneumolysin. The low-transmission serotype 23F exhibits low pneumolysin activity, resulting in impaired TNFR2 + Treg responses. This, in turn, enhances activation of the γδT17-neutrophil axis, which promotes pneumococcal clearance and disrupts 23F transmission. Conclusion This study demonstrates an unexpected but key role of TNFR2 + Tregs in transmission of hypervirulent pneumococci.