Search

Background: Lymphocyte activation gene 3 (LAG-3) is one of the immune checkpoint molecules, negatively regulating the T-cell reactions. The present study investigated the role of LAG-3 in sepsis-induced T-lymphocyte disability., Methods: Mice sepsis was induced by cecal ligation and puncture (CLP). LAG-3 expression on some immune cells were detected 24 hours after CLP. LAG-3 knockout and anti-LAG-3 antibody were applied to investigate the effects on the survival, bacterial clearance. Cytokine levels, T-cell counts, and the presence of apoptosis (in blood, spleen, and thymus) were also determined. In vitro T-cell apoptosis, interferon γ secretion, and proliferation were measured. The expression of interleukin 2 receptor on T cells was also determined after CLP., Results: LAG-3 was up-regulated on CD4+/CD8+ T, CD19+ B, natural killer, CD4+CD25+ regulatory T cells and dendritic cells. Both LAG-3 knockout and anti-LAG-3 antibody had a positive effect on survival and on blood or peritoneal bacterial clearance in mice undergoing CLP. Cytokine levels and T-cell apoptosis decreased in anti-LAG-3 antibody-treated mice. Induced T-cell apoptosis decreased, whereas interferon γ secretion and proliferation were improved by anti-LAG-3 antibody in vitro. Interleukin 2 receptor was up-regulated on T cells in both wild-type and LAG-3-knockout mice undergoing CLP., Conclusions: LAG-3 knockout or anti-LAG-3 antibody blockade protected mice undergoing CLP from sepsis-associated immunodysfunction and may be a new target for the treatment., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Summary: Objectives: To characterize the expression profiles of genes in purified monocytes from septic patients during systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS), and then to investigate the potential mechanism of monocyte deactivation. Methods: Lipopolysaccharides (LPS)-induced cytokine responses, phagocytosis assay and migration assay were performed in monocytes from SIRS patients, CARS patients and healthy volunteers (n = 8). After functional assays, each pair of samples from the same group was pooled into one for gene expression analysis. All new samples (n = 4) were hybridized on NimbleGen human gene expression 12 × 135 K microarrays, and selected genes were validated by real-time polymerase chain reaction. Pathway analysis and Gene Ontology analysis were performed on differentially expressed genes using Agilent GeneSpring (version 11.0). Results: A set of genes related to pro-inflammation, phagocytosis, chemotaxis, antigen presentation, and anti-apoptosis were significantly down-regulated, while some genes associated with pro-apoptosis and anti-inflammation were up-regulated instead on monocytes from CARS patients compared with SIRS patients and healthy volunteers. Monocytes from CARS patients showed impaired production of TNF-α and IL-6, and increased release of IL-10 when stimulated by LPS. Functional analysis confirmed reduced phagocytosis and migratory activity of monocytes from CARS patients. Human leukocyte antigen-DR (HLA-DR) measurements demonstrated decreased expression of HLA-DR on monocytes from CARS patients. Conclusion: Monocytes from CARS patients exhibited significant changes in mRNA expression of genes associated with phagocytosis, antigen presentation, inflammatory response, cell migration, and apoptosis, which might cause deactivation of monocytes during CARS. [ABSTRACT FROM AUTHOR]