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General presentation

The PD-1 protein, also known as CD279, is the program cell-death 1 protein which plays a particular role in the activation of T-lymphocytes. This cell surface receptor can be found on pro-B cells and T cells and belongs to the immunoglobulin super family. It can bind two ligands: PD-L1 and PD-L2 and when it is related to PD-L2, it results an inhibition of T-cells and cytokine production. Even if it structure is not yet totally characterized, PD-1 seems to be a promising target for clinical applications^[1].

History

In 1992, PD-1 cDNA was discovered by Ishida et al^[2]. Thanks to the studies on PD-1-deficient mice on the C57BL/6 background, PD-1 begun to be understood, even if its precise function still unknown at this time. Still, the role of PD-1 in deficiency and autoimmunity was suggested^[3].
In 1994, Shinohara et al^[4]. (1994) succeeded in characterizing the human homolog of the mouse gene and the similarity was of 60% for amino acids, with a well-conserved tyrosine-kinase association motif.
In 1997, Finger et al^[5]. (1997) achieved the complete sequencing of the cDNA of the PD-1 gene.
Since 2014 and 2015, some drugs are proposed to prevent the binding of the ligands of PD-1 and favorized its role in the activation of T-lymphocytes: PD-1 is now a new promising target for immunotherapy and cancer research.

Structure

This gene is located on the chromosome 2 at the location: 2q37.3 (genomic coordinates: 2:241,849,880-241,858,907)^[6]. It measured 2106 bp and possessed 5 exons^[7].[1] The PD-1 predicted protein possessed 288 amino acid.[2] The PD-1 structure included an (), a () and an intracellular tail. This tail comported two phosphorylation site located in an immunoreceptor tyrosine based inhibitory motif and an immunoreceptor tyrosine-based switch motif^[8]. That suggests that PD-1 negatively regulates T cells receptor signals. It is agreeing with binding of Tyrosine-protein phosphatase non-receptor type 6 (SHP-1) and Tyrosine-protein phosphatase non-receptor type 11 (SHP-2) to the cytoplasmic tail of PD-1 after ligand binding. PD-1 ligation up-regulates E3-ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation^[9].

Functions and related pathway

Programmed Death 1 (PD-1) is a transmembrane protein that is expressed by T cells. As a consequence, and thanks to its structure described above, this receptor is able to transmit information into the T cell through the recognition of its ligands. It is mainly involved in the control of autoimmunity, since it usually allows the mediation of self-reacting T cells^[10]. The immune system has to be balanced between being efficient against various antigen presenting cells (APC) and remaining able to recognise the host cells. Part of this second ability is ensured by PD-1. It can bind mainly two ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2)^[11].
The intracellular consequences at a molecular level of this recognition is known to inhibit the activation of the T cell presenting the involved PD-1 by triggering SHP1, a tyrosine phosphatase^[12]. SHP1 is then responsible for the dephosphorisation of a component of the CD3-TCR complex (CD3-zeta), which normally allows the T cell to trigger an intracellular pathway when an antigen is recognized[3]. Through this transduction inhibition, not only is the T cell inactivated but the regulation of the actin of its cytoskeleton is perturbed as well^[13].
As a consequence, T cell dies by apoptosis and the immune response is repressed. These mechanisms are responsible for autoimmune mediation, however cancer cells often upregulate PD-L1 expression, consequently blocking the immune response in the tumour microenvironment^[14].

Inhibitor

The PD-1 protein is an inhibitory of the immune response by T cells when it interacts with (). These ligands belong to the B7 family^[15].PD-L1 is up-regulated when macrophage or dendritic cells are in contact with LPS or during a Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. PD-L1 is also up-regulated on T cells and B cells upon TCR and B cell receptor signalling. When PD1 is inhibits it upregulated a lot of genes in CD8-positive T cells. These gene activation provokes an upregulation of the transcription factor BATF. The high expression of BATF impairs cell proliferation and cytokine secretion whereas BATF reduces PD1 inhibition^[16].
PD-L2 expression is rarest than PD-L1 expression. This ligand is expressed by DCs and a few tumors. The binding of PDL2 provokes an inhibition of T cells proliferation and cytokine production^[17].

Pathologies and clinical applications

PD-1 negatively regulates immune response and is used for immunotherapy and particularly for cancers and as tumor repressor^[18]. Nivolumab (Opdivo, Bristol-Myers Squibb), an antibody-drug, was then developed to block the activity of this receptor and is given to treat metastatic melanomas^[19]. This drug prevents the binding of the PD-1 ligands which permits T-cells to work. For the same applications, Pembrolizumab (Keytruda, MK-3475, Merck)) has been developed and is used since March 2015 in the UK for advanced melanoma and it is in the clinical trials in the US. Others drugs are being developed such as Pidilizumab (CT-011, Cure Tech), BMS 936559 (Bristol Myers Squibb), and MPDL328OA (Roche)^[20].

PD-1 is also a target for HIV treatment. In fact, as it is acting on T-cell immune responses, it has been discovered that PD-1 is upregulated on T-cells of seropositive patients of HIV^[21][22][23]. Because of this, it is part of an HIV-drug association in long-term suppressive Antiretroviral Therapy (ART). In fact, during the stage of infection, PD-1 on HIV-specific T-cells is expressed and this expression acts like a marker for the infection progression^[24].

The PD-1 receptor is also involved in the regulation of the gut microbiota by selecting IgA plasma cell repertoires^[25] . Indeed, when an individual is PD-1 deficient, the IgAs produced have a less efficiency bacteria-binding and it results in an alteration of microbial community in the gut. So PD-1 plays a role in regulation of antibody diversification required for the maintenance of intact mucosal barrier^[26].

References