Regulatory T cells mediate the decreased susceptibility of males to Pseudomonas aeruginosa infection

Abstract

Abstract Background Sex hormones have been shown to play a role in the susceptibility of female patients with CF to P. aeruginosa chronic infection; however, the cellular mechanisms responsible for such sex-based imbalance are poorly understood. Accordingly, the aim of this study was to assess the role of the female sex hormone estrogen in a murine model of P. aeruginosa induced lung infection and to elucidate the cellular immune mechanisms involved. Methods The bacterial burden and inflammatory parameters following intranasal infections with P. aeruginosa were compared in male and female mice. Female mice were treated with anastrozole, which lowers estradiol, and the impact on survival assessed. Infection in male and female RAG1−/− mice, which lack T and B lymphocytes, and Foxp3DTR/GFP mice, in which Tregs can be selectively depleted, were also compared. Results We demonstrate that female adult mice are more susceptible to P. aeruginosa lung infection, compared to that of males, while this effect was not evident in pre-pubescent mice. Pre-treatment of female adult mice with anastrozole, resulted in increased survival and a greater ability to control P. aeruginosa induced lung infection, as evidenced by reduced bacterial burden in the lung and reduced levels of serum IL-6. This increased susceptibility of adult female mice to P. aeruginosa was not seen during infection in RAG1−/− mice, or following depletion of regulatory T cells (Tregs) in Foxp3DTR/GFP mice. In male mice, there was a significant increase in IL-6 levels following Treg depletion, demonstrating liberation from regulation, which did not occur in female mice. Conclusions This data demonstrates, for the first time, that the increased susceptibility of female mice to P. aeruginosa-induced lung infection is a result of the reduced action of Tregs. The potential benefits of targeting Treg activity in CF warrants further investigation in prevention and treatment of P. aeruginosa infection.