Background The highly inflammatory immune response to Streptococcus pneumoniae infection can result in complications such as sepsis and Acute Respiratory Distress Syndrome. Macrophages are an important source of the inflammatory cytokines that activate epithelial and endothelial cells, resulting in a loss of barrier integrity. Regulatory T cells (Tregs) are a population of anti-inflammatory cells that modulate macrophage activity and are protective against invasive pneumococcal disease in mice.^1,2

Aims To characterise the in vitro effects of Tregs on the macrophage inflammatory response to S. pneumoniae and to observe Treg recruitment to the site of intradermal injection of UV-killed S. pneumoniae in a human model.

Results Preliminary data suggest that co-culture of human monocyte-derived macrophages (MDMs) with CD4⁺CD25⁺CD127^- Tregs reduced MDM TNFα production by at least 45% (One-way ANOVA p<0.01) and IL-6 production by at least 52% (One-way ANOVA p<0.01) 72 hours after initial infection with S. pneumoniae TIGR4 strain (MOI of 2, ratio of 1 Treg to 3 MDMs). Separation of Tregs from the MDMs during co-culture using transwell inserts prevented the suppressive effects of the Tregs. Using a novel human model of S. pneumoniae challenge involving intradermal injection of UV-killed S. pneumoniae into the forearm of healthy volunteers, we demonstrated that Tregs accumulated at the site of injection within 48 hours, increasing from undetectable Treg population at 4 hours to constituting approximately 33% of CD4 cells by 48 hours.

Conclusion Preliminary data suggest that Tregs modulate the MDM inflammatory response to S. pneumoniae in a contact-dependent manner, and track to the site of intradermal injection of the UV-killed bacteria in human volunteers.

References

1. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+FoxP3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci 2007;104(49):19446–51.

2. Neill DR, Fernandes VE, Wisby L, Haynes AR, Ferreira DM, Laher A, Strickland N, Gordon SB, Denny P, Kadioglu A, Andrew PW. T regulatory cells control susceptibility to invasive pneumococcal pneumonia in mice. PLoS Pathog 2012;8(4):e1002660.