Programmed death 1 (PD-1) is an inhibitor protein receptor for the immune system and has been shown to be upregulated in animal models of critical illness as well as after trauma and in burn victims in humans. It is believed that PD-1 may play a role in the immune dysfunction seen in surgical critical illness. However, although prior studies have associated changes in PD-1 expression with altered immune cell function, it is not known if a correlation with clinical status exists. We therefore aimed to describe a potential role for PD-1 in the immune dysfunction seen in critically ill trauma and surgical patients. This is an observational cohort study. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated on critically ill and injured trauma and surgical intensive care unit patients from a tertiary care/level I trauma center. Blood was drawn within 24 h of establishment of diagnosis and admission to the intensive care unit to measure circulating cytokine levels, as well as PD-1 expression on circulating cells. Main outcome measures included PD-1 expression on leukocytes and the relationship to physiological dysfunction (APACHE II) as well as the correlation of PD-1 expression and interleukin 10 levels among patients with severe physiological dysfunction. Samples were collected from 90 critically ill surgical patients. Among patients with severe physiological dysfunction (APACHE II >20), there were increased numbers of granulocytes (median, 144 vs. 90 cells/μL; P = 0.037) and monocytes (median, 12 vs. 6 cells/μL; P = 0.022) with PD-1 expression. In addition, among patients with an APACHE II score of greater than 20, there was a larger percentage of CD3 cells (44% vs. 29%; P = 0.015) expressing PD-1. When only patients with an APACHE II score greater than 20 were assessed, PD-1 expression on monocytes correlated positively with interleukin levels in the serum (r = 0.525, P = 0.05). Variability in the expression of PD-1 on leukocytes in critical surgical illness correlates with physiological dysfunction and suggests that PD-1 may be a valuable tool in the assessment of immune dysfunction following trauma or severe surgical insult.

Invariant Natural Killer T-cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. iNKT-cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. iNKT-cells have been shown to modulate various mediators of the innate immune system, including macrophages. Herein 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(PD-1). PD-1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT-cells. PD-1 has been associated with markers of human critical illness. PD-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. iNKT−/− mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT−/− mice were co-cultured with wild type iNKT-cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by PD-1, and these peritoneal iNKT-cells appear critical to regulation of peritoneal macrophage phagocytic function. iNKT-cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis.