SPLENIC INVARIANT NATURAL KILLER T CELLS PLAY A SIGNIFICANT ROLE IN THE RESPONSE TO POLYMICROBIAL SEPSIS

Abstract

ABSTRACT Background: Sepsis is marked by a dysregulated immune response to an infection. Invariant natural killer T cells (iNKT cells) are a pluripotent lymphocyte subpopulation capable of affecting and coordinating the immune response to sepsis. The spleen is an important site of immune interactions in response to an infection. Splenic iNKT cells have emerged as important potential frontline mediators of chronic immune response. There are few data addressing the role splenic of iNKT cells in response to intra-abdominal polymicrobial sepsis. Methods: The cecal ligation and puncture model was used to create intra-abdominal sepsis in 8- to 12-week-old wild-type, iNKT−/−, or programmed cell death receptor-1 (PD-1)−/− mice. Twenty-four hours later, spleens were harvested. Flow cytometry was used for phenotyping using monoclonal antibodies. Cell sort was used to isolate iNKT cells. A macrophage cell line was used to assess iNKT cell–phagocyte interactions. Enzyme-linked immunosorbent assay was used for cytokine analysis. Results: Splenic iNKT-cell populations rapidly declined following induction of sepsis. Within iNKT-cell−/− mice, a distinct baseline hyperinflammatory environment was noted. Within wild type, sepsis induced an increase in splenic IL-6 and IL-10, whereas in iNKT−/− mice, there was no change in elevated IL-6 levels and a noted decrease in IL-10 expression. Further, following sepsis, PD-1 expression was increased upon spleen iNKT cells. With respect to PD-1 ligands upon phagocytes, PD-1 ligand expression was unaffected, whereas PD-L2 expression was significantly affected by the presence of PD-1. Conclusions: Invariant natural killer T cells play a distinct role in the spleen response to sepsis, an effect mediated by the checkpoint protein PD-1. Given that modulators are available in clinical trials, this offers a potential therapeutic target in the setting of sepsis-induced immune dysfunction.