Pro-Inflammatory Th1 and Th17 Cells Are Suppressed During Human Experimental Endotoxemia Whereas Anti-Inflammatory IL-10 Producing T-Cells Are Unaffected

Abstract

ObjectiveSepsis is one of the leading causes of the deaths in hospitals. During sepsis, patients are exposed to endotoxemia, which may contribute to the dysregulation of the immune system frequently observed in sepsis. This dysregulation leads to impaired pro-inflammatory responses and may increase the risk for secondary infections in sepsis. The experimental human endotoxemia model is widely used as a model system to study the acute effects of endotoxemia. Under physiological circumstances, the immune system is tightly regulated. Effector T-cells exert pro-inflammatory function and are restrained by regulatory T-cells (Tregs), which modulate pro-inflammatory effector responses. Endotoxemia may induce inadequate Treg activity or render effector T-cells dysfunctional. It was the aim of the study to investigate effector T-cell and Treg responses in an experimental human endotoxemia model.MethodsIn a cross-over designed placebo-controlled study, 20 healthy male volunteers received an intravenous injection of either lipopolysaccharide (LPS) (0.8 ng/kg body weight) or a placebo (saline 0.9%). CD3+ T-cells, CD4+ T-cells, CD8+ T-cells, and intracellular cytokine profiles were measured with flow cytometry at baseline and at repeated points after LPS/placebo injection. Complete blood cell counts were obtained with an automated hematology analyzer and cytokines were quantified by ELISA.ResultsCirculating neutrophils were significantly increased 2 h after LPS injection (p < 0.001) while absolute number of CD3+ T-cells, CD4+ T-cells, and CD8+ T-cells decreased (p < 0.001). Effector T-helper-cells (THs) showed a significant—but transient—decrease of pro-inflammatory IFNγ, interleukin (IL)-2, TNFα, and IL-17A production after LPS injection (p < 0.001). In contrast, the frequency of Treg and the capacity to produce IL-10 were unchanged (p = 0.21).ConclusionEffector THs fail to produce pro-inflammatory Th1-/Th17-associated cytokines after LPS challenge. In contrast, IL-10 production by Treg is not affected. Thus, endotoxemia-induced suppression of pro-inflammatory THs might be considered as a contributing factor to immunoparalysis in sepsis.

The correlation between Jun N-terminal kinase pathway-associated phosphatase and Th1 cell or Th17 cell in sepsis and their potential roles in clinical sepsis management

“…However, the modulatory role of JKAP on Th1 and Th17 cell functions should be assessed by more animal or cell experiments. (2) As for the elevation of Th1 and Th17 proportions and their correlations with more severe disease in sepsis patients, it is reasonable because Th1 and Th17 cells play a role that promotes the disease progression in sepsis as reported by the previous studies [21,[23][24][25].…”

Influences of Regulation of miR-126 on Inflammation,Th17/Treg Subpopulation Differentiation, and Lymphocyte Apoptosis through Caspase Signaling Pathway in Sepsis

“…During the development of sepsis, the core problems are the hyperactivity and paralysis of immune function (immune imbalance), which are related to the functional state of immune cells and the release of inflammatory factors [22]. The dysfunction of immune cells is often caused by the imbalance of T lymphocyte subsets.…”

CD4 T Cell Responses and the Sepsis-Induced Immunoparalysis State

“…Losses in CD4 T cell subsets impacts CD4 T cell-mediated help provided to other cell types, as was recently demonstrated for reduced antibody production resulting from CD4 T cell-dependent B cell responses, which was caused in part by reduced Tfh differentiation following immunization of septic hosts ( 38 ). In addition, the effects of sepsis on the ability to produce effector cytokines (IL-10 in the case of Treg) may be less severe for Treg than for other CD4 T cell subsets ( 87 ). The impact of increased Treg cell representation following sepsis has been debated, as some have correlated it with worse outcomes ( 88 ), while others have suggested it correlates with better outcomes and immunity ( 89 – 91 ).…”