PD-1
Encyclopedia
Programmed Death 1, or PD-1, is a Type I membrane protein
of 268 amino acid
s. 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. The intracellular tail contains two phosphorylation
sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. PD-1 is expressed on the surface of activated T cells, B cell
s, and macrophage
s, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
family. PD-L1 protein is upregulated on macrophages and dendritic cell
s (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.
and dilated cardiomyopathy
on the C57BL/6 and BALB/c backgrounds, respectively. In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion. Reduced T cell proliferation correlated with attenuated IL-2 secretion, which can be rescued by addition of cross-linking anti-CD28 antibodies or exogenous IL-2. Together, these data suggest that PD-1 negatively regulates T cell responses. Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4 and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV model of chronic infection, Rafi Ahmed’s group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.
As CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecule PD-1 has been independently explored as a target for immunotherapy
. The 2C TCR recognizes the peptide SIYRYYGL in the context of H 2kb. 2C CD8 T cells incubated with IFN-γ treated B16 targets expressing SIYRYYGL peptide poorly lyse their targets and secrete low levels of IL-2. However, PD-1 knockout 2C T cells have heightened cytolytic capacity and IL-2 secretion, suggesting that PD-1 negatively regulates anti-tumor CD8 T cell responses. Similarly, P815 mastocytoma, which does not express PD-L1 unless treated with IFN-γ, can be transduced to express PD-L1, resulting in inhibition of in vitro CD8-mediated cytotoxicity and enhanced in vivo tumor growth. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1). Together, these data suggest that expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighti pathway as a target for immunotherapy.
Said et al. showed that triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.
Membrane protein
A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...
of 268 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. PD-1 is a member of the extended CD28/CTLA-4 family of T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. PD-1 is expressed on the surface of activated T cells, B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s, and macrophage
Macrophage
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, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
Ligands
PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7B7 (protein)
B7 is a type of peripheral membrane protein found on activated antigen presenting cells that, when paired with either a CD28 or CD152 surface protein on a T cell, can produce a costimulatory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively...
family. PD-L1 protein is upregulated on macrophages and dendritic cell
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...
s (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.
Function
Many studies indicate that PD-1 and its ligands negatively regulate immune responses. First, PD-1 knockout mice develop lupus-like glomerulonephritisGlomerulonephritis
Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys...
and dilated cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
on the C57BL/6 and BALB/c backgrounds, respectively. In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion. Reduced T cell proliferation correlated with attenuated IL-2 secretion, which can be rescued by addition of cross-linking anti-CD28 antibodies or exogenous IL-2. Together, these data suggest that PD-1 negatively regulates T cell responses. Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4 and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV model of chronic infection, Rafi Ahmed’s group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.
As CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecule PD-1 has been independently explored as a target for immunotherapy
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
. The 2C TCR recognizes the peptide SIYRYYGL in the context of H 2kb. 2C CD8 T cells incubated with IFN-γ treated B16 targets expressing SIYRYYGL peptide poorly lyse their targets and secrete low levels of IL-2. However, PD-1 knockout 2C T cells have heightened cytolytic capacity and IL-2 secretion, suggesting that PD-1 negatively regulates anti-tumor CD8 T cell responses. Similarly, P815 mastocytoma, which does not express PD-L1 unless treated with IFN-γ, can be transduced to express PD-L1, resulting in inhibition of in vitro CD8-mediated cytotoxicity and enhanced in vivo tumor growth. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1). Together, these data suggest that expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighti pathway as a target for immunotherapy.
Said et al. showed that triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.