PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction

Abstract

IntroductionLymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown.MethodsSepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T cells, B cells and monocytes were measured 24 hours after CLP or sham surgery. Additionally, the effects of anti-PD-L1 antibody on lymphocyte number, apoptosis of spleen and thymus, activities of caspase-8 and caspase-9, cytokine production, bacterial clearance, and survival were determined.ResultsExpression of PD-1 on T cells, B cells and monocytes and PD-L1 on B cells and monocytes were up-regulated in septic animals compared to sham-operated controls. PD-L1 blockade significantly improved survival of CLP mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of lymphocytes, increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, decreased IL-10 production, and enhanced bacterial clearance.ConclusionsPD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Anti-PD-L1 antibody administration may be a promising therapeutic strategy for sepsis-induced immunosuppression.

Programmed Death Ligand 1 on Burkholderia pseudomallei–Infected Human Polymorphonuclear Neutrophils Impairs T Cell Functions

“…However, our findings of reduced T cell responses mediated by PD-L1 on B. pseudomalleiinfected PMNs are consistent with the increasing involvement of this pathway in regulating antimicrobial responses to acute infections (24,37). This is strongly supported by a report demonstrating that IFN-g-stimulated neutrophils after acute inflammatory responses suppress T cell function via their expression of PD-L1 on neutrophils (21).…”

“…blockade of the PD-1 pathway decreased mortality in clinically relevant animal models of bacterial sepsis (24).…”

“…In HIV-1 infection, there is evidence that this pathway also suppresses IFN-g production by T cells from HIV patients (21). Some studies have suggested a pathological role for PD-1/PD-L1 by reducing microbial clearance and innate inflammatory responses, but accelerating T cell apoptosis in sepsis (22)(23)(24). PD-L1 is reportedly expressed on a variety of different cell types, both hematopoietic and nonhematopoietic cells, including T cells and myeloid cells such as dendritic cells and monocytes, and its expression is highly upregulated during inflammatory states (20).…”

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

“…Common to most septic patients is the increased expression of PD‐1 on T cells during the progression from hyper‐inflammation to hypo‐inflammation. Recent studies showed that disruption of the PD‐1/PD‐L1 axis either by genetic deletion or by pharmacological manipulation improves survival in bacterial and fungal murine sepsis 46, 47. Boomer et al showed that PD‐1 expression was increased in CD4 and CD8 T cells, whereas PD‐L1 expression was increased in antigen‐presenting cells as well as in the spleen and lungs of septic patients.…”

A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

“…Recent studies have reported that PD-L1 expression also increased in mice with sepsis induced by CLP (12,36). Additionally, blockade of PD-L1 by antibody suppressed intestinal inflammation and prevented the development of colitis in mice (13) …”