Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a
protein that in humans is encoded by the ''CD274''
gene.
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1
transmembrane protein that has been speculated to play a major role in suppressing the
adaptive arm of
immune systems during particular events such as
pregnancy, tissue
allografts,
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
and other disease states such as
hepatitis. Normally the adaptive immune system reacts to
antigens that are associated with immune system activation by exogenous or endogenous
danger signals
Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated m ...
. In turn, clonal expansion of
antigen-specific
CD8+ T cells and/or
CD4+ helper cells
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule
PD-1 transmits an inhibitory signal based on interaction with phosphatases (
SHP-1 or
SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM).
This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene
Bcl-2.
History
PD-L1 was characterized at the Mayo Clinic as an immune regulatory molecule, B7-H1 . Later, this molecule was renamed as PD-L1 because it was identified as a ligand of PD-1 Several human cancer cells expressed high levels of B7-H1, and blockade of B7-H1 reduced the growth of tumors in the presence of immune cells. At that time, it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity. In 2003, B7-H1 was shown to be expressed on Myeloid cells as checkpoint protein and was proposed as potential target in cancer immunotherapy in human clinic.
Binding
PD-L1 binds to its receptor,
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
dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...
K
d, is 770 nM. PD-L1 also has an appreciable affinity for the costimulatory molecule
CD80 (B7-1), but not
CD86 (B7-2).
CD80's affinity for PD-L1, 1.4 µM, is intermediate between its affinity for
CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
and
CTLA-4 (4.0 µM and 400 nM, respectively). The related molecule
PD-L2
Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is a protein that in humans is encoded by the ''PDCD1LG2'' gene. PDCD1LG2 has also been designated as CD273 (cluster of differentiation 273). PDCD1LG2 is an immune checkpoint receptor l ...
has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger K
d of 140 nM).
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
PD-1 on T cells delivers a signal that inhibits
TCR-mediated activation of
IL-2
The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...
production and T cell proliferation. The mechanism involves inhibition of
ZAP70 phosphorylation and its association with
CD3ζ
T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the ''CD247'' gene.
Some older literature mention a similar protein called " ...
.
PD-1 signaling attenuates
PKC-θ
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and th ...
activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors
NF-κB and
AP-1, and for production of IL-2. PD-L1 binding to PD-1 also contributes to ligand-induced TCR down-modulation during antigen presentation to naive T cells, by inducing the up-regulation of the E3 ubiquitin ligase CBL-b.
Regulation
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 and monocytes
PD-L1 is notably expressed on
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s. In the mouse, it has been shown that classically activated macrophages (induced by type I
helper T cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s or a combination of
LPS
LPS may refer to:
Science and medicine
* Lipopolysaccharide (Endotoxin)
* Levator palpebrae superioris muscle
Schools
* Leighton Park School in Reading, England
* Lexington Public Schools, a school district in Massachusetts, USA
* Lincoln P ...
and
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
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.
It was also shown that PD-L1 is constituvely expressed on mouse Ly6C
lo nonclassical
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
in steady state.
Role of microRNAs
Resting human
cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by
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. Whereas the Epstein-Barr viral (EBV) latent membrane protein-1 (LMP1) is a known potent inducer of PD-L1, the EBV miRNA miR-BamH1 fragment H rightward open reading frame 1 (BHRF1) 2-5p has been shown to regulate LMP1 induced PD-L1 expression.
Epigenetic regulation
PD-L1 promoter DNA methylation may predict survival in some cancers after surgery.
Clinical significance
Cancer
PD-L1 is shown to be highly expressed in a variety of malignancies, particularly lung cancer. In order to anticipate the effectiveness of gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoints, PD-L1 might be employed as a prognostic marker and a target for anti-cancer immunity. i.e. upregulation of PD-L1 may allow cancers to evade the host immune system. For example, an analysis of 196 tumor specimens from patients 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.
Many
PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.
Clinically available examples include
durvalumab
Durvalumab (trade name Imfinzi) is an FDA-approved immunotherapy for cancer, developed by Medimmune/AstraZeneca. It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 ...
,
atezolizumab and
avelumab.
In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1.
CAR-T and
NK cells targeting PD-L1 are being evaluated for treating cancer. pSTAT-1 and PDL-1 expressions also strongly correlate in prostate cancer.
Upregulation of PD-L1 on immune cells (especially
myeloid
Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...
cells) can also lead to formation of an immunosuppressive environment in a highly localized manner that also allow the cancer cells to proliferate.
''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
PD-1/PD-L1 interaction is thought to play a role in preventing desctructive autoimmunity, especially during inflammatory conditions. The best example is in the stomach, where PD-1 expression protects the
gastrin
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
Gastrin ...
expressing
G-cells
In anatomy, the G cell or gastrin cell, is a type of cell in the stomach and duodenum that secretes gastrin. It works in conjunction with gastric chief cells and parietal cells. G cells are found deep within the pyloric glands of the stomach antrum ...
from the immune system during
Helicobacter pylori-provoked inflammation.
But also a variety of pre-clinical studies support the notion that the PD-1/PD-L1 interaction is implicated in autoimmunity.
NOD mice Non-obese diabetic or NOD mice, like biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated w ...
, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop 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
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE). Studying isolated
PBMC
A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neu ...
from healthy children, immature
myeloid dendritic cells and
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
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.
See also
*
Cluster of differentiation
*
Co-stimulation
*
Immune tolerance
References
External links
*
*
{{B7 Family
Clusters of differentiation