CD4+CD25+ Regulatory T Cells Attenuate Lipopolysaccharide-Induced Systemic Inflammatory Responses and Promotes Survival in Murine Escherichia coli Infection

Abstract

It is well established that CD4CD25 regulatory T cells (Tregs) downregulate inflammatory immune responses and help to maintain immune homeostasis. Recent reports have shown that ligation of germline encoded pattern recognition receptors such as Toll-like receptors can stimulate Tregs and therefore implicate Tregs in the pathophysiology of sepsis and other inflammatory diseases. In this report, we show that injection of lipopolysaccharide (LPS) leads to expansion of CD4CD25FoxP3 Tregs, suggesting that these cells may play an important role in immune regulation in LPS-induced acute inflammation. Indeed, genetic or immunological inhibition of Treg function using mice lacking functional Tregs (CD25 KO mice) or anti-CD25 monoclonal antibody (anti-CD25 mAb), respectively, led to acute death in an otherwise nonlethal LPS challenge. This was accompanied by exaggerated production of proinflammatory cytokines. Strikingly, adoptive transfer of CD4CD25 Tregs to CD25 KO mice before LPS challenge rescues mice from death. Unlike LPS, depletion of Tregs followed by concanavalin A (Con A) challenge does not result in mortality, suggesting that Treg depletion does not globally influence all models of acute inflammation. We authenticate our findings by showing that depletion of Tregs leads to mortality in a nonlethal Escherichia coli challenge accompanied by elevated serum levels of proinflammatory cytokines. Collectively, our results indicate that in addition to regulation of LPS-induced acute inflammation, Tregs help to improve bacterial clearance and promote survival in an acute model of bacterial infection.

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine

“…Cambos et al [124 ]showed that Tregs help to control excessive inflammation in lethal Plasmodium chabaudi adami infection, in which mortality is associated with a systemic inflammatory response. In line with the observation of Heuer et al [123], our laboratory recently showed that the immunological or genetic inhibition of Treg function, using an anti-CD25 monoclonal antibody treatment or mice lacking functional Tregs (CD25 KO mice), respectively, was detrimental in a sepsis model of bacterial infection or LPS-induced acute inflammatory response [125]. This was accompanied by exaggerated production of proinflammatory cytokines including IL-1β, IL-6, IL-12, TNF and CCL2.…”

“…This was accompanied by exaggerated production of proinflammatory cytokines including IL-1β, IL-6, IL-12, TNF and CCL2. Strikingly, adoptive transfer of Tregs into CD25 KO mice before LPS challenge rescues mice from death [125]. Furthermore, we demonstrated the mechanism by which Tregs regulate inflammation during sepsis.…”

“…We showed that adoptive transfer of Tregs rescued mice from LPS-induced mortality [125]. Treg therapy has also been established in animal models of several immune-mediated inflammatory diseases like type 1 diabetes [127] and graft-versus-host disease (GVHD) [128].…”

“…Interestingly, mice with an inactivating knock-in mutation in the p110δ gene (p110δ KI) have impaired function and dramatically fewer numbers of Tregs [139]. Since Tregs have been shown to be beneficial in sepsis [123,124,125,126], it is conceivable that the enhanced susceptibility of p110δ KI mice might be related to this impaired function and reduced Treg numbers. Indeed, we found that adoptive transfer of wild-type Tregs into p110δ KI mice rescued them from lethal LPS challenge.…”

“FoxP3 Hunting” during Infection with Francisella Tularensis

“…It has also been recently reported that LPS from Escherichia coli, during infection, increases the number of host CD4+CD25+FoxP3+ cells and removal of these cells exacerbates disease. It was suggested that the T cells were controlling reg the pro-inflammatory response and that removal of this regulation caused an overactive and damaging immune response (25). An important role ofT cells reg towards host survival has also been shown in sepsis (28).…”