PD-1 and PD-L1 contribute to liver dysfunction in a murine cecal ligation and puncture (CLP) model of sepsis, but virtually nothing is known about PD-L2's role in sepsis.
Serum sPD-1 levels were positively correlated with the severity of sepsis, sPD-L1 levels, PD-1 expression on CD4 or CD8 T cells, and PD-L1 expression on monocytes.
Previous studies have revealed that programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) play critical roles in the immunosuppression phase induced by sepsis.
Here we show that a "priming insult" for iARDS, such as non-lethal hemorrhagic shock alone, produced a marked increase in lung EC PD-L1 as well as blood leukocyte PD-1 expression, and when combined with a subsequent "trigger event" (polymicrobial sepsis), not only induced marked iARDS but significant mortality.
We first validated relevance of our CyTOF results by highlighting established immune hallmarks of sepsis, such as decreased monocyte HLA-DR expression and increased expressions of PD1 and PD-L1 on CD4 T cells and monocytes.
Upregulation of programmed death-1 (PD-1) receptor on T cells and programmed cell death ligand-1 (PD-L1) on myeloid cells contribute to immune dysfunction in nonburn-related sepsis.
Oxygen Saturation on Admission Is a Predictive Biomarker for PD-L1 Expression on Circulating Monocytes and Impaired Immune Response in Patients With Sepsis.
PD-L1/programmed cell death-1 (PD-1) blocking and knockdown assays on tolerant monocytes from both patients with sepsis and the in vitro model reverted the impaired adaptive response.
Trials assessing the therapeutic benefit of IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF) and antibodies against programmed cell death protein 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) for the treatment of sepsis are in progress.
Additionally, we explore how the up-regulation of PD-1 and/or PD-L1 expression on not only adaptive immune cells (e.g., T cells), but also on innate immune cells (e.g., macrophages, monocytes, and neutrophils), as well as nonimmune cells during sepsis and/or shock contributes to functional alterations often with detrimental sequelae.
Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival.
Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis.
English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated.
In this study, mice with CLP-induced sepsis were treated with farnesyltransferase inhibitor (FTI-277), and PD-L1 expression on septic spleen lymphocytes was examined.
To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability, tissue cytokine levels were assessed.