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From Proteopedia

Revision as of 21:07, 29 January 2016

Structure of PD-1

General presentation of the protein:

The PD-1 protein, also known as CD279, is a program cell-death 1 protein which plays a particular role in the activation of T-lymphocytes. This protein of 288 amino acids is encoded by a cDNA gene of 2,106 base pairs long located in the chromosome 2 for human. 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.

History :

In 1992, PD-1 cDNA was discovered by Ishida et al. 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. In 1994, Shinohara et al. (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. (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.

Functions and related pathway

Programmed Death 1 (PD1) is a protein involved in the regulation of the immune system. It 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. 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 PD1. It can bind mainly two ligands, programmed death ligand 1 (PDL1) and programmed death ligand 2 (PDL2). The intracellular consequences at a molecular level of this recognition is known to inhibit the activation of the T cell presenting the involved PD1 by triggering SHP1, a tyrosine phosphatase. 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. Through this transduction inhibition, not only is the T cell inactivated but the regulation of the actin of its cytoskeleton is perturbed as well.

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. 

Clinical applications:

PD-1 negatively regulates immune response and is used for immunotherapy and particularly for cancers and as tumor repressor. 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. 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).