Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function.

Invariant natural killer T cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. Invariant natural killer T cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. Invariant natural killer T cells have been shown to modulate various mediators of the innate immune system, including macrophages. We demonstrate sepsis-inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by programmed death receptor 1. Programmed death receptor 1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT cells. Programmed death receptor 1 has been associated with markers of human critical illness. Programmed death receptor 1-deficient iNKT cells failed to demonstrate similar migration. To the extent that iNKT cells affected peritoneal macrophage function, we assessed peritoneal macrophages' ability to phagocytose bacteria. Invariant natural killer T(-/-) mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT(-/-) mice were cocultured with wild-type iNKT cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by programmed death receptor 1, and these peritoneal iNKT cells appear critical to regulation of peritoneal macrophage phagocytic function. Invariant natural killer T cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis.