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TNFR2+ regulatory T cells protect against bacteremic pneumococcal pneumonia by suppressing IL-17A-producing γδ T cells in the lung

Streptococcus pneumoniae is a pathogen of global morbidity and mortality. Pneumococcal pneumonia can lead to systemic infections associated with high rates of mortality. We find that, upon pneumococcal infection, pulmonary Treg cells are activated and have upregulated TNFR2 expression. TNFR2-deficie...

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Published in:Cell reports (Cambridge) 2023-02, Vol.42 (2), p.112054-112054, Article 112054
Main Authors: Xu, Rong, Jacques, Laura C., Khandaker, Shadia, Beentjes, Daan, Leon-Rios, Miguel, Wei, Xiaoqing, French, Neil, Neill, Daniel R., Kadioglu, Aras
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Language:English
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Summary:Streptococcus pneumoniae is a pathogen of global morbidity and mortality. Pneumococcal pneumonia can lead to systemic infections associated with high rates of mortality. We find that, upon pneumococcal infection, pulmonary Treg cells are activated and have upregulated TNFR2 expression. TNFR2-deficient mice have compromised Treg cell responses and highly activated IL-17A-producing γδ T cell (γδT17) responses, resulting in significantly enhanced neutrophil infiltration, tissue damage, and rapid development of bacteremia, mirroring responses in Treg cell-depleted mice. Deletion of total Treg cells predominantly activate IFNγ-T cell responses, whereas adoptive transfer of TNFR2+ Treg cells specifically suppress the γδT17 response, suggesting a targeted control of γδT17 activation by TNFR2+ Treg cells. Blocking IL-17A at early stage of infection significantly reduces bacterial blood dissemination and improves survival in TNFR2-deficient mice. Our results demonstrate that TNFR2 is critical for Treg cell-mediated regulation of pulmonary γδT17-neutrophil axis, with impaired TNFR2+ Treg cell responses increasing susceptibility to disease. [Display omitted] •Pneumococcus activates lung Treg cells with upregulated TNFR2•TNFR2+ Treg cells are associated with resistance to pneumococcal infection•TNFR2+ Treg cells specifically suppress pulmonary IL-17A-producing γδ T cells•Dysregulated γδT17 response correlates with excessive neutrophil influx to the lung Xu et al. show that pulmonary Treg cells are activated by pneumococci via TNFR2, and lack of Treg cells or TNFR2 promotes bacterial dissemination from lungs to blood. TNFR2+ Treg cells confer resistance to pneumococcal infection by controlling pulmonary γδT17 cell responses and neutrophil recruitment.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.112054