Programmed cell death protein 1 and PD-L1, PD-L2


The PD-1 protein in humans is encoded by the PDCD1 gene.[9][10] PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells.[10] PD-1 binds two ligands, PD-L1 and PD-L2.



In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1.[11][12] In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.[12]



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.[21][22] In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN- secretion.[16] IFN- is a key pro-inflammatory cytokine that promotes T cell inflammatory activity. Reduced T cell proliferation was also correlated with attenuated IL-2 secretion and together, these data suggest that PD-1 negatively regulates T cell responses.[23]

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 viral vector 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.[24]

Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells.[19][20] 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.[5][25] 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.[26]

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.[10]

Overexpression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion (e.g. in chronic infection or cancer).[5][27]


What is a receptor ligand?

A molecule that binds to a receptor is called a ligand, and can be a protein or peptide (short protein), or another small molecule such as a neurotransmitter, hormone, pharmaceutical drug, toxin, or parts of the outside of a virus or microbe. The endogenously designated -molecule for a particular receptor is referred to as its endogenous ligand.


Receptors and ligands come in many forms, but they all have one thing in common: they come in closely matched pairs, with a receptor recognizing just one (or a few) specific ligands, and a ligand binding to just one (or a few) target receptors.