Effect of PD-1

Abstract

Invariant natural killer T-cells (iNKT) are a subset of T-cells that play a regulatory role in sepsis. Following cecal ligation and puncture (CLP), iNKT cells emigrate from the liver and into the circulation and peritoneum in a manner dependent upon co-inhibitory molecule Programmed Cell Death Receptor 1 (PD-1). We hypothesized that the effect of PD-1 on iNKT cell emigration was dependent upon the direct PD-1:PD-L1 interaction and that PD-1 and PD-L1 would play a role in chemotaxis and chemokine receptor expression. Adoptive transfer of Vybrant-labelled wild type (WT) cells showed the donor iNKT cells migrated from the liver to the peritoneum following CLP, but PD-L1 deficient donor iNKT cells did not. In a chemotaxis assay, WT iNKT cells chemotaxed to CXCL12, but PD-1 and PD-L1 deficient iNKT cells did not. Using flow cytometry to evaluate chemokine receptor expression, peritoneal iNKT expression of CXCR4 increased following CLP in the WT, PD-1, and PD-L1 deficient animals, and CXCR6 increased in the WT and PD-1 deficient animals. In conclusion here we document that the hepatic emigration of iNKT cells following CLP to the peritoneum appears dependent upon the direct PD-1:PD-L1 interaction, however, while PD-1 and PD-L1 appear to play a role in chemotaxis, this is unlikely a reflection of iNKT cell chemokine receptor expression changes.

Program Cell Death Receptor-1-Mediated Invariant Natural Killer T-Cell Control of Peritoneal Macrophage Modulates Survival in Neonatal Sepsis

“…i NKT cells regulate clearance of the peritoneal bacterial septic burden and affect influx of key immune cells. Specifically, within adults, we have noted that this i NKT cell regulation of the immune response to sepsis is controlled by the regulatory checkpoint protein PD-1 ( 16 ), a finding not previously observed in neonates.…”

“…The CS model at our institution is modification ( 16 ) of the model previously described by Wynn et al ( 17 ). In brief, a naive WT adult donor mouse (C57BL/6J) was euthanized and cecal contents were harvested.…”

A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis

“…Subsequently, Wang et al (106) showed that PMNs from CLP mice and patients diagnosed with severe sepsis exhibited a substantial rise in their PD-L1 expression, correlating with increased morbidity in the septic patients. Additionally, these cells, via direct contact, were capable of inducing a marked increase in lymphocytic cell death/dysfunction (another common feature of the septic animal/patient) as well as altering the migrational functionality of the cell (a dysfunction also noted by Young et al (107) in septic mouse i NKT cells) (22). More recently, Patera et al (53) have further found that peripheral blood PMNs from septic patients that expressed high levels of PD-L1 exhibited a decline in their capacity to phagocytize bacteria, a reduction of CD168 expression and a poor production of TNF-α in response to stimuli.…”

“…i NKT-cells are capable of both a Th1 and a Th2 response and interact with a diverse array of immune cells serving to both positively and negatively regulate the immune and inflammatory response i NKT-cells are capable of trafficking both within the liver in response to a sterile injury (74), in and out the lung in response to an infection (75). As well as distally to a septic source in the abdomen (76). i NKT-cells are themselves regulated by co-inhibitory/checkpoint proteins, most notably PD-1.…”

“…Initial activation of i NKT-cells is associated with increased PD-1 expression upon i NKT-cells (77) (Figure 4, Component [2]). Young et al (76) showed that direct ligation of PD-1 with its ligand PD-L1 is essential to trafficking and migration of i NKT-cells and PD-1 is essential to regulation of chemokine receptor expression upon i NKT-cells. Conversely, repeated stimulation of PD-1 upon i NKT-cells has been shown to induce anergy (78) a mechanism that is believed to have developed to protect against an over-exuberant i NKT-cell driven immune response.…”