CD274
Encyclopedia
Programmed cell death 1 ligand 1 (PD-L1) also known as cluster of differentiation (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 immune system
during particular events such as pregnancy, tissue 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 lymph node
s or spleen which triggers a proliferation of antigen
-specific CD8+ T cell
. The formation of PD-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 Bcl-2
.
, 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
Kd, is 770nM. Interestingly, 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, 1.4µM, is intermediate between its affinities for CD28
and 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-L1, up-regulated on activated CD4 T-cells, can bind to PD-1 expressed on monocytes and induces IL-10 production by the later.
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 NF-κB and AP-1, and for production of IL-2.
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.
s. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cell
s or a combination of LPS
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.
found that high tumor expression of B7-H1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. Ovarian cancer
patients with higher expression of B7-H1 had a significantly poorer prognosis than those with lower expression of B7-H1. An inverse correlation was observed between B7-H1 expression and intraepithelial CD8+ T-lymphocyte count, suggesting that B7-H1 on tumor cells may suppress antitumor CD8+ T cells.
, 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 Systemic lupus erythematosus
. Studying isolated PBMC
from healthy children, immature myeloid dendritic cells
and 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CD274 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Programmed death ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
that has been speculated to play a major role in suppressing the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
during particular events such as pregnancy, tissue 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 lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s or spleen which triggers a proliferation of antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
-specific CD8+ T cell
Cytotoxic T cell
A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
. The formation of PD-1
PD-1
Programmed Death 1, or PD-1, is a Type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail...
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 Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
.
Binding
PD-L1 binds to its receptor, PD-1PD-1
Programmed Death 1, or PD-1, is a Type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail...
, 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
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
Kd, is 770nM. Interestingly, PD-L1 also has an appreciable affinity for the costimulatory molecule CD80
CD80
Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival...
(B7-1), but not CD86
CD86
Cluster of Differentiation 86 is a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival...
(B7-2). CD80's affinity for PD-L1, 1.4µM, is intermediate between its affinities for CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
and CTLA-4
CTLA-4
CTLA4 also known as CD152 is a protein that plays an important regulatory role in the immune system...
(4.0µM and 400nM, respectively). The related molecule PD-L2
PDCD1LG2
Programmed cell death 1 ligand 2 is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273 ....
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-L1, up-regulated on activated CD4 T-cells, can bind to PD-1 expressed on monocytes and induces IL-10 production by the later.
Signaling
Engagement of PD-L1 with its receptor PD-1PD-1
Programmed Death 1, or PD-1, is a Type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail...
on T cells delivers a signal that inhibits TCR
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
-mediated activation of IL-2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
production and T cell proliferation. The mechanism involves inhibition of ZAP70
ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
phosphorylation and its association with CD3ζ
CD247
T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 is a protein that in humans is encoded by the CD247 gene.- Genomics :...
. PD-1 signaling attenuates PKC-θ
PRKCQ
Protein kinase C theta type is an enzyme that in humans is encoded by the PRKCQ gene.-Interactions:PRKCQ has been shown to interact with FYN, GLRX3, AKT1 and VAV1.PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway....
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.
By Interferons
Upon IFN-γInterferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
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
IRF1
Interferon regulatory factor 1 is a protein that in humans is encoded by the IRF1 gene.- Function :Interferon regulatory factor 1 was the first member of the interferon regulatory transcription factor family identified...
, the interferon regulatory factor. Type I interferons
Interferon type I
Human type I interferons comprise a vast and growing group of IFN proteins.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor that consists of IFNAR1 and IFNAR2 chains....
can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.
On Macrophages
PD-L1 is notably expressed on macrophageMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cell
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
s or a combination of LPS
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
and interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
) greatly upregulate PD-L1. Alternatively, macrophages activated by IL-4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
(alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by STAT1
STAT1
STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...
-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
In humans, resting cholangiocytes express B7-H1 mRNA, but not B7-H1 protein. B7-H1 mRNA is subject to translational suppression by microRNA miR-513, which is expressed in resting cholangiocytes. Upon treatment with interferon-gamma, miR-513 was down-regulated (shown by micro-array analysis), thereby lifting suppression of B7-H1 protein. In this way, interferon-gamma can induce B7-H1 protein expression by inhibiting gene-mediated suppression of mRNA translation.Cancer
It appears that upregulation of B7-H1 is a mechanism that cancers can employ to evade the host immune system. An analysis of 196 tumor specimens from patients with Renal cell carcinomaRenal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
found that high tumor expression of B7-H1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. Ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
patients with higher expression of B7-H1 had a significantly poorer prognosis than those with lower expression of B7-H1. An inverse correlation was observed between B7-H1 expression and intraepithelial CD8+ T-lymphocyte count, suggesting that B7-H1 on tumor cells may suppress antitumor CD8+ T cells.
Listeria monocytogenes
In a mouse model of intracellular infection, L. monocytogenes induced B7-H1 protein expression in T cells, NK cells, and macrophages. B7-H1 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 B7-H1 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. NOD miceNOD mice
Non-obese diabetic or NOD mice, like the Biobreeding rat, are used as an animal model for type 1 diabetes.- History :Non-obese diabetic mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus...
, 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 Systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
. Studying isolated PBMC
PBMC
A peripheral blood mononuclear cell is any blood cell having a round nucleus. For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells , B cells...
from healthy children, immature myeloid dendritic cells
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
and 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.