Programmed cell death protein 1 also known as PD1 is a 288 amino acid cell surface protein
molecule that in humans is encoded by the PDCD1 gene.
PDCD1 has also been designated as CD279.
This gene encodes a cell surface membrane protein of the immunoglobulin superfamily.
This protein is expressed on T cells and pro-B cells and plays a role in their fate/ differentiation.
Structure Programmed death 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.
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 cells, and macrophages, 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 B7 family.
PD-L1 protein is upregulated on macrophages and dendritic cells 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 Several lines of evidence suggest that PD-1
and its ligands negatively regulate immune responses.
PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis 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 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, highlighting this 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.
Clinical significance In mice, expression of this gene is induced
in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo
apoptosis.
Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy
and died from congestive heart failure.
These studies suggest that this gene product may also be important in T cell function and
contribute to the prevention of autoimmune diseases.
Cancer Monoclonal antibodies targeting PD-1 that
boost the immune system are being developed for the treatment of cancer.
Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction
between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical
antitumor activity.
One such anti-PD-1 antibody drug, nivolumab, produced complete or partial responses in
non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with
a total of 296 patients.
Colon and pancreatic cancer did not have a response.
HIV Drugs targeting PD-1 may augment immune responses
and/or facilitate HIV eradication.
See Also Pembrolizumab approved by the FDA in Sept
2014 to treat metastatic melanoma.
References
Further reading
External links PDCD1 protein, human at the US National Library
of Medicine Medical Subject Headings This article incorporates text from the United
States National Library of Medicine, which is in the public domain.