Pneumococcal transmission is driven by TNFR2+ regulatory T-cells

Beentjes, D, Murray, J, French, N ORCID: 0000-0003-4814-8293, Vipond, C, Xu, R and Kadioglu, A ORCID: 0000-0003-1137-6321 (2026) Pneumococcal transmission is driven by TNFR2+ regulatory T-cells Frontiers in Immunology, 17. 1840694-. ISSN 1664-3224, 1664-3224

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	Nasopharynx, Animals, Mice, Streptococcus pneumoniae, Pneumococcal Infections, Disease Models, Animal, Bacterial Proteins, Receptors, Tumor Necrosis Factor, Type II, Streptolysins, Female, T-Lymphocytes, Regulatory, Th17 Cells
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences > Clinical Infection, Microbiology & Immunology
Depositing User:	Symplectic Admin
Date Deposited:	21 Jul 2026 14:42
Last Modified:	07 Sep 2026 08:53
DOI:	10.3389/fimmu.2026.1840694
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3199478
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