Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients

Abstract

IntroductionStudies on the role of programmed death-1(PD-1) and its main ligand (PD-L1) during experimental models of sepsis have shown that the PD-1/PD-L1 pathway plays a pathologic role in altering microbial clearance, the innate inflammatory response and accelerated apoptosis in sepsis. However, the expression of PD-1 and PD-L1 and their role during the development of immune suppression in septic patients have not been elucidated. The present study was designed to determine whether the expression of PD-1 and PD-L1 is upregulated in septic shock patients and to explore the role of this pathway in sepsis-induced immunosuppression.MethodsNineteen septic shock patients and 22 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis in lymphocyte subpopulations and PD-1/PD-L1 expression on peripheral T cells, B cells and monocytes were measured using flow cytometry. Apoptosis of T cells induced by TNFα or T-cell receptor ligation in vitro and effects of anti-PD-L1 antibody administration were measured by flow cytometry. CD14+ monocytes of septic shock patients were purified and incubated with either lipopolysaccharide, anti-PD-L1 antibody, isotype antibody, or a combination of lipopolysaccharide and anti-PD-L1 antibody or isotype antibody. Supernatants were harvested to examine production of cytokines by ELISA.ResultsCompared with healthy controls, septic shock induced a marked increase in apoptosis as detected by the annexin-V binding and active caspase-3 on CD4+ T cells, CD8+ T cells and CD19+ B cells. Expression of PD-1 on T cells and of PD-L1 on monocytes was dramatically upregulated in septic shock patients. PD-1/PD-L1 pathway blockade in vitro with anti-PD-L1 antibody decreased apoptosis of T cells induced by TNFα or T-cell receptor ligation. Meanwhile, this blockade potentiated the lipopolysaccharide-induced TNFα and IL-6 production and decreased IL-10 production by monocytes in vitro.ConclusionsThe expression of PD-1 on T cells and PD-L1 on monocytes was upregulated in septic shock patients. The PD-1/PD-L1 pathway might play an essential role in sepsis-induced immunosuppression.

Reduction of Immunocompetent T Cells Followed by Prolonged Lymphopenia in Severe Sepsis in the Elderly*

“…However, PD-1 is also thought to be a marker of T cell aging in humans and mice (31). Our findings show increased expression of PD-1 on CD4+ and CD8+ T cells in elderly patients with sepsis when compared with that of elderly HDs, which is consistent with a previous report that PD-1 on T cells and programmed death ligand-1 (PD-L1) on monocytes are dramatically upregulated in a cohort of patients with septic shock (32). Interestingly, it has been suggested that PD-1/PD-L1 might be a therapeutic target to reverse immunosuppression in sepsis.…”

Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

“…Hence, it has been postulated that anti-PD-1 and anti-PD-L1 therapies could have similar beneficial effects in patients suffering from sepsisinduced immune dysfunction (115). Patients with severe sepsis show increased levels of PD-1 and PD-L1 on their monocyte and T lymphocyte populations (116). Recent studies demonstrated neutrophil PD-L1 upregulation on neutrophils from septic mice and humans, resulting in the potentiation of lymphocyte apoptosis through contact inhibition, which correlated with outcome (117).…”

Critical Illness–Induced Immune Suppression: Current State of the Science

“…Patients with sepsis whose cells demonstrate increased cell surface inhibitory molecule expression are at increased risk for secondary infections and mortality, providing evidence for another distinguishing marker of immune suppression. 47,48 Last, regulatory T cells are a highly immunosuppressive subset of T cells that are known to produce large quantities of anti-inflammatory cytokines. They appear to be resistant to apoptosis and can predominate in the subacute phase of sepsis in adults 49 although this has not been seen in children.…”