TNFR2+ regulatory T cells protect against bacteremic pneumococcal pneumonia by suppressing IL-17A-producing y? 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 infec-tion, pulmonary Treg cells are activated and have upregulated TNFR2 expression. TNFR2-deficient mice have compromised Treg cell responses and highly activated IL-17A-producing y8 T cell (y8T17) responses, result-ing 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 IFNy-T cell responses, whereas adoptive transfer of TNFR2+ Treg cells specifically suppress the y8T17 response, suggesting a targeted control of y8T17 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 y8T17-neutrophil axis, with impaired TNFR2+ Treg cell responses increasing susceptibility to disease.

Automated summary

Streptococcus pneumoniae is a highly morbid and mortal pathogen. Activation of pulmonary Treg cells with upregulated TNFR2 expression occurs upon pneumococcal infection. Deficiency in TNFR2 compromises Treg cell responses, leading to highly activated IL-17A-producing y8 T cell responses and increased susceptibility to disease. Blocking IL-17A at early stage of infection improves survival in TNFR2-deficient mice.