Targeting Lymphocyte Activation Gene 3 to Reverse T-Lymphocyte Dysfunction and Improve Survival in Murine Polymicrobial Sepsis

Abstract

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 gamma 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 gamma 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. Lymphocyte activation gene 3 (LAG-3) was up-regulated on some immune cells in septic mice. Both LAG-3 knockout and anti-LAG-3 antibody had positive effects on survival rate, bacterial clearance, cytokine levels, and T cell apoptosis, interferon gamma secretion and proliferation.