Neutralization of interleukin-10 or transforming growth factor-β decreases the percentages of CD4+CD25+Foxp3+ regulatory T cells in septic mice, thereby leading to an improved survival

Objectives. To investigate the role of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in septic conditions, and to examine the potential of targeting them for the treatment of sepsis. Background. Sepsis-induced immunosuppression has long been considered a factor in late mortality of patients with sepsis. Although Tregs are central to the maintenance of immunologic homeostasis and tolerance, little is known, about Treg-mediated immunosuppression in the late stages of sepsis. Methods. Peripheral blood mononuclear cells (MNCs) in septic patients and liver or spleen MNCs collected after a cecal ligation and puncture (CLP) model in C57BL/6 mice were examined to evaluate the roles of Tregs and the correlation of transforming growth factor (TGF)-beta or interleukin (IL)-10 with their activity. We next examined the effects of neutralization of TGF-beta or IL-10 on the percentages of Tregs in T cells and the survival rates of septic mice. Results. The percentages of Tregs in peripheral blood lymphocytes were significantly increased in patients with sepsis, and there was a significantly positive correlation. between serum IL-10 levels and the percentage of Tregs. CLP injury increases the percentages of Tregs in the CD4(+) T cells in the spleen, and there was a significantly positive correlation between the percentages of Tregs and the serum IL-10 or TGF-beta levels. The neutralization of TGF-beta or IL-10 decreased the percentages of Tregs in CD4+ T restored the percentages of CD4(+) T cells in spleen MNCs, and improved survival rates in septic mice. Conclusion. We found an increase in the percentages of Tregs in peripheral blood circulating CD4(+) T cells from patients with sepsis, and in splenic MNCs from septic mice, and observed that regulation of Tregs by neutralizing IL-10 or TGF-beta might represent a novel strategy for treating the immunosuppressive conditions in sepsis. (Surgery 2012;151:313-22.)