PD-L1

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a is_associated_with::protein that in humans is encoded by the CD274 is_associated_with::gene.

Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 is_associated_with::transmembrane protein that has been speculated to play a major role in suppressing the is_associated_with::immune system during particular events such as pregnancy, tissue is_associated_with::allografts, autoimmune disease and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens where there is some accumulation in the is_associated_with::lymph nodes or spleen which triggers a proliferation of is_associated_with::antigen-specific CD8+ T cell. The formation of is_associated_with::PD-1 receptor / PD-L1 or B7.1 receptor /PD-L1 ligand complex transmits an inhibitory signal which reduces the proliferation of these CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene is_associated_with::Bcl-2.

Binding
PD-L1 binds to its receptor, is_associated_with::PD-1, found on activated T cells, B cells, and myeloid cells, to modulate activation or inhibition. The affinity between PD-L1 and PD-1, as defined by the is_associated_with::dissociation constant Kd, is 770nM. Interestingly, PD-L1 also has an appreciable affinity for the costimulatory molecule is_associated_with::CD80 (B7-1), but not is_associated_with::CD86 (B7-2). CD80's affinity for PD-L1, 1.4µM, is intermediate between its affinities for is_associated_with::CD28 and is_associated_with::CTLA-4 (4.0µM and 400nM, respectively). The related molecule PD-L2 has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger Kd of 140nM). Said et al. showed that PD-1, up-regulated on activated CD4 T-cells, can bind to PD-L1 expressed on monocytes and induces IL-10 production by the latter.

Signaling
Engagement of PD-L1 with its receptor is_associated_with::PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its association with CD3ζ. PD-1 signaling attenuates PKC-θ activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors is_associated_with::NF-κB and AP-1, and for production of IL-2.

By Interferons
Upon IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells. The PD-L1 gene promoter region has a response element to IRF-1, the interferon regulatory factor. Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.

On Macrophages
PD-L1 is notably expressed on is_associated_with::macrophages. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cells or a combination of LPS and is_associated_with::interferon-gamma) greatly upregulate PD-L1. Alternatively, macrophages activated by IL-4 (alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by is_associated_with::STAT1-deficient knock-out mice that STAT1 is mostly responsible for upregulation of PD-L1 on macrophages by LPS or interferon-gamma, but is not at all responsible for its constitutive expression before activation in these mice.

Role of MicroRNAs
Resting human is_associated_with::cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by is_associated_with::microRNA miR-513. Upon treatment with interferon-gamma, miR-513 was down-regulated, thereby lifting suppression of PD-L1 protein. In this way, interferon-gamma can induce PD-L1 protein expression by inhibiting gene-mediated suppression of mRNA translation.

Cancer
It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with is_associated_with::renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. is_associated_with::Ovarian cancer patients with higher expression of PD-L1 had a significantly poorer prognosis than those with lower expression. PD-L1 expression correlated inversely with intraepithelial CD8+ T-lymphocyte count, suggesting that PD-L1 on tumor cells may suppress antitumor CD8+ T cells. This has encouraged development of is_associated_with::PD-L1 inhibitors which have started clinical trials. The effect might be tumor type dependant; a study on patients with non-small cell is_associated_with::lung cancer showed that greater PD-L1 protein and mRNA expression is associated with increased local lymphocytic infiltrate and longer survival.

Listeria monocytogenes
In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells). This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.

Autoimmunity
The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. is_associated_with::NOD mice, an animal model for autoimmunity in that they exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to have precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).

In humans, PD-L1 was found to have altered expression in pediatric patients with is_associated_with::Systemic lupus erythematosus. Studying isolated is_associated_with::PBMC from healthy children, immature myeloid dendritic cells and is_associated_with::monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5 day time course, expressing this protein only during disease remissions. This may be one mechanism whereby peripheral tolerance is lost in SLE.