Targeting LAG-3 reverses T lymphocytes dysfunction and improves survival in murine polymicrobial sepsis.

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 lymphocytes disability. METHODS: Mice sepsis was induced by cecal ligation and puncture (CLP). LAG-3 expression on some immune cells were detected 24h after CLP. LAG-3-knockout mice and anti-LAG-3 antibody were applied to investigate the effects on the survival, bacterial clearance. Cytokines level, T cell counts and apoptosis (blood/spleen/thymus) were also determined. In vitro T cells apoptosis, IFN-gamma secretion, proliferation were detected. IL-2 receptor (IL-2R) on T cells was also determined after CLP. RESULTS: LAG-3 upregulated on CD4+/CD8+ T, CD19+ B, NK, CD4+ CD25+ Treg cells and DCs. Both LAG-3-knockout and anti-LAG-3 antibody had a positive effect on the survival, blood/peritoneal bacterial clearance in CLP mice. Cytokines level and T cells apoptosis decreased in anti-LAG-3 antibody-treated mice. Induced T cells apoptosis decreased while the IFN-gamma secretion and proliferation were improved by anti-LAG-3 antibody in vitro. IL-2R on T cells upregulated both in wild-type and LAG-3 deficiency CLP mice. CONCLUSIONS: LAG-3 diminish or anti-LAG-3 antibody blockade protected CLP mice from sepsis-associated immunodysfunction and maybe a new target for the treatment.