Adoptive Transfer of In Vitro-Stimulated CD4+CD25+ Regulatory T Cells Increases Bacterial Clearance and Improves Survival in Polymicrobial Sepsis

Abstract

Regulatory CD4+CD25+ T cells (Tregs) suppress autoimmune and inflammatory diseases through mechanisms that are only partly understood. Previous studies suggest that Tregs can suppress bacterially triggered intestinal inflammation and respond to LPS through TLRs with enhanced suppressive activity. In this study, we have used murine cecal ligation and puncture as a model of polymicrobial sepsis to explore the effects of adoptive transfer of Tregs on septic outcome. Adoptive transfer of in vitro-stimulated Tregs in both prevention and therapeutic modes significantly improved survival of cecal ligation and puncture mice. Furthermore, the effect was dependent on both the number of Tregs adoptively transferred and the presence of host T cells. Animals that received stimulated Tregs had significantly increased peritoneal mast cells and peritoneal TNF-α production. More importantly, adoptive transfer of in vitro-stimulated Tregs significantly improved bacterial clearance, which resulted in improved survival. Our results suggest a novel role for Tregs in sepsis.

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

“…They are increased in percentage in the peripheral blood of sepsis patients compared with that of healthy controls (46), and their number is increased in the spleen of septic mice (47). Whereas their deletion does modify the outcome of septic mice (47), their transfer improved survival in the polymicrobial model of sepsis (48) and contributed to normalize resolution of lung injury in mice exposed to LPS (49). However, they also contribute to the immunosuppressive environment associated with sepsis (50).…”

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

“…Interestingly, we found that Tregs from septic mice had increased suppressor cell activity ex vivo when compared with Tregs from sham-treated mice. It is known that activation of Tregs by anti-CD3 engagement can increase their suppressive properties (20). Recently, engagement of TLRs by pathogen-associated molecular patterns on Tregs has also been shown to induce their proliferation and activation, while causing an increase in their suppressor cell function (15,16).…”

“…However, whether these Tregs suppress T effector cell proliferation was not examined. Interestingly, expanding the endogenous population of activated Tregs by adoptive transfer before or following the initiation of polymicrobial sepsis improved outcome by enhancing peritoneal and mast cell TNF-␣ production and bacterial clearance (20). At the same time, whether endogenous Tregs modulate outcomes in sepsis is unknown.…”

T Cell Suppression in Burn and Septic Injuries

“…In a similar burn model Treg were found to inhibit TGF-and CD4+ proliferation in a cell-to-cell contact (Ni Choileain N, et al, 2006). In contrast a study of polymicrobial cecal-ligation-puncture (CLP) peritonitis model Tregs were found to have protective effects (Heuer JG et al, 2005). The mechanisms by which these small lymphocyte subsets regulate or control remains subject of future studies but final effector responses are modulated through cascade of cytokines, like IFN-, IL-4, IL-6, IL-10 and TGF-.…”