Abstract
IntroductionSevere sepsis is characterized by an initial hyper-inflammatory response that may progress to an immune-suppressed state associated with increased susceptibility to nosocomial infection. Analysis of samples obtained from patients who died of sepsis has identified expression of specific inhibitory receptors expressed on lymphocytes that are associated with cell exhaustion. The objective of this study was to prospectively determine the pattern of expression of these receptors and immune cell function in patients with acute sepsis.MethodsTwenty-four patients with severe sepsis were enrolled within 24 hours of the onset of sepsis, as were 12 age-matched healthy controls. Peripheral blood was obtained at enrollment and again seven days later. Immune cell subsets and receptor expression were extensively characterized by quantitative flow cytometry. Lymphocyte function was assayed by stimulated cytokine secretion and proliferation assays. Results were also correlated to clinical outcome.ResultsAt the onset of severe sepsis, patients had decreased circulating innate and adaptive immune cells and elevated lymphocyte expression of receptors associated with cell activation compared to controls. Samples analyzed seven days later demonstrated increased expression of the inhibitory receptors CTLA4, TIM-3 and LAG-3 on T lymphocytes accompanied by decreased expression of the IL-7 receptor. Functional assays revealed impaired secretion of interferon γ following stimulation in vitro, which was reversible by incubation overnight in fresh media. Impaired secretion of IFNγ correlated with death or development of secondary infection.ConclusionsLymphocytes from patients with acute sepsis upregulate expression of receptors associated with cell exhaustion, which may contribute to the immune suppressed state that occurs in protracted disease. Therapy that reverses T cell exhaustion may restore immune function in immunocompromised patients and improve survival in sepsis.
Highlights
Severe sepsis is characterized by an initial hyper-inflammatory response that may progress to an immune-suppressed state associated with increased susceptibility to nosocomial infection
Our findings demonstrated a reduction in circulating innate (NK and dendritic cells (DC)) and adaptive (CD4+) immune cells in samples obtained at enrollment, consistent with reports demonstrating significant lymphopenia and cell death early in the course of disease [7,8,9,10,34,35,36,37,38,39]
We found the expression of the inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) on both CD4+ and CD8+ T cells and T cell immunoglobulin mucin-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3) on CD4 + T cells increased on cells from septic patients
Summary
Severe sepsis is characterized by an initial hyper-inflammatory response that may progress to an immune-suppressed state associated with increased susceptibility to nosocomial infection. A consistent decrease in HLA-DR expression, an essential molecule for antigen presentation, and expression of co-stimulatory molecules such as CD86 has been observed [11,12,13] This initial phase of activation and apoptosis may be accompanied by increased numbers of suppressor cells, such as regulatory T cells (Treg), myeloid derived suppressor cells (MDSCs) and the recently described CD11b +/CD62L+ population of granulocytes, as a mechanism for controlling the adaptive immune response and returning the body to homeostasis [14,15,16,17,18,19]
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