Programmed cell death 1

Programmed cell death protein 1, also known as PD-1 and CD279 (is_associated_with::cluster of differentiation 279), is a is_associated_with::protein that in humans is encoded by the PDCD1 is_associated_with::gene. PD-1 is a cell surface receptor that belongs to the is_associated_with::immunoglobulin superfamily and is expressed on is_associated_with::T cells and pro-is_associated_with::B cells. PD-1 binds two ligands, is_associated_with::PD-L1 and PD-L2.

PD-1, functioning as an is_associated_with::immune checkpoint, plays an important role in down regulating the is_associated_with::immune system by preventing the activation of T-cells, which in turn reduces is_associated_with::autoimmunity and promotes is_associated_with::self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting is_associated_with::apoptosis (programmed cell death) in is_associated_with::antigen specific T-cells in is_associated_with::lymph nodes while simultaneously reducing apoptosis in is_associated_with::regulatory T cells (suppressor T cells).

A new class of drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used to treat cancer.

Structure
Programmed death 1 is a type I is_associated_with::membrane protein of 268 is_associated_with::amino acids. PD-1 is a member of the extended is_associated_with::CD28/is_associated_with::CTLA-4 family of is_associated_with::T cell regulators. The protein's structure includes an extracellular IgV domain followed by a is_associated_with::transmembrane region and an intracellular tail. The intracellular tail contains two is_associated_with::phosphorylation sites located in an is_associated_with::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, is_associated_with::B cells, and is_associated_with::macrophages, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.

Ligands
PD-1 has two is_associated_with::ligands, is_associated_with::PD-L1 and PD-L2, which are members of the B7 family. PD-L1 protein is upregulated on macrophages and is_associated_with::dendritic cells (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 is_associated_with::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 is_associated_with::knockout mice have been shown to develop lupus-like is_associated_with::glomerulonephritis and dilated is_associated_with::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 is_associated_with::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 is_associated_with::thymocytes undergo is_associated_with::apoptosis. Mice deficient for this gene bred on a BALB/c background developed is_associated_with::dilated cardiomyopathy and died from is_associated_with::congestive heart failure. These studies suggest that this gene product may also be important in is_associated_with::T cell function and contribute to the prevention of is_associated_with::autoimmune diseases.

Cancer
is_associated_with::Monoclonal antibodies targeting PD-1 that boost the is_associated_with::immune system are being developed for the treatment of is_associated_with::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, is_associated_with::nivolumab, (Opdivo - Bristol Myers Squibb), 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.

is_associated_with::Nivolumab (Opdivo, Bristol-Myers Squibb), which also targets PD-1 receptors, was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic is_associated_with::melanoma.

is_associated_with::Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic is_associated_with::melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects.It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. Other drugs in early stage development targeting PD-1 receptors: is_associated_with::Pidilizumab (CT-011, Cure Tech),, is_associated_with::BMS 936559 (Bristol Myers Squibb), and is_associated_with::MPDL328OA (Roche)

HIV
Drugs targeting PD-1 may augment immune responses and/or facilitate is_associated_with::HIV eradication.