TY - JOUR
T1 - A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis
AU - Boomer, Jonathan S.
AU - Shuherk-Shaffer, Jennifer
AU - Hotchkiss, Richard S.
AU - Green, Jonathan M.
N1 - Funding Information:
The authors thank Christine Deppong, Traci Bricker, Brandy Rannals and Seth Crockford for advice and technical support of this project. The authors thank Ann Doyle for patient enrollment and clinical data capture. This project was funded by grants R21HL104985 (JMG), GM044118 (RSH) and GM055194 9RSH) from the National Institutes of Health. We thank the Center for Biomedical Informatics (CBMI) for use of ClinPortal and CaTissue. This publication was made possible through funding support for the CBMI from the Alvin J. Siteman Cancer Center (SCC) at Washington University School of Medicine, Barnes-Jewish Hospital in St. Louis, MO and the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis. The SCC is supported in part by the National Institutes of Health’s NCI Cancer Center Support Grant #P30 CA91842 and the ICTS is funded by the National Institutes of Health’s NCATS Clinical and Translational Science Award (CTSA) program (Grant # UL1 RR024992).
PY - 2012/6/28
Y1 - 2012/6/28
N2 - Introduction: 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. 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.Methods: Twenty-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.Results: At 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.Conclusions: Lymphocytes 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.
AB - Introduction: 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. 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.Methods: Twenty-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.Results: At 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.Conclusions: Lymphocytes 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.
UR - http://www.scopus.com/inward/record.url?scp=84862766869&partnerID=8YFLogxK
U2 - 10.1186/cc11404
DO - 10.1186/cc11404
M3 - Article
C2 - 22742734
AN - SCOPUS:84862766869
SN - 1364-8535
VL - 16
JO - Critical Care
JF - Critical Care
IS - 3
M1 - R112
ER -