PD-L1

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.[5]

CD274
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD274, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1, PDL1, CD274 molecule, Programmed cell death ligand 1, hPD-L1
External IDsOMIM: 605402 MGI: 1926446 HomoloGene: 8560 GeneCards: CD274
Gene location (Human)
Chr.Chromosome 9 (human)[1]
Band9p24.1Start5,450,503 bp[1]
End5,470,566 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

29126

60533

Ensembl

ENSG00000120217

ENSMUSG00000016496

UniProt

Q9NZQ7

Q9EP73

RefSeq (mRNA)

NM_001314029
NM_001267706
NM_014143

NM_021893

RefSeq (protein)

NP_001254635
NP_001300958
NP_054862

NP_068693

Location (UCSC)Chr 9: 5.45 – 5.47 MbChr 19: 29.37 – 29.39 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM).[6] This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.

History

PD-L1 was characterized at the Mayo Clinic as an immune regulatory molecule, B7-H1. Later this molecule was renamed as PD-L1 because it was identified as a ligand of PD-1[7] Several human cancer cells expressed high levels of B7-H1, and blockade of B7-H1 reduced the growth of tumors in the presence of immune cells. At that time it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity.[8] In 2003 B7-H1 was shown to be expressed on Myeloid cells as checkpoint protein and was proposed as potential target in cancer immunotherapy in human clinic. [9]

Binding
Binding interactions

PD-L1 binds to its receptor, PD-1, found on activated T cells, B cells, and myeloid cells, to modulate activation or inhibition. The affinity between PD-L1 and PD-1, as defined by the dissociation constant Kd, is 770nM. PD-L1 also has an appreciable affinity for the costimulatory molecule CD80 (B7-1), but not CD86 (B7-2).[10] CD80's affinity for PD-L1, 1.4µM, is intermediate between its affinities for CD28 and CTLA-4 (4.0µM and 400nM, respectively). The related molecule PD-L2 has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger Kd of 140nM). Said et al. showed that PD-1, up-regulated on activated CD4 T-cells, can bind to PD-L1 expressed on monocytes and induces IL-10 production by the latter.[11]

Signaling

Engagement of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its association with CD3ζ.[12] PD-1 signaling attenuates PKC-θ activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors NF-κB and AP-1, and for production of IL-2. PD-L1 binding to PD-1 also contributes to ligand-induced TCR down-modulation during antigen presentation to naive T cells, by inducing the up-regulation of the E3 ubiquitin ligase CBL-b.[13]

Regulation

By interferons

Upon IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells.[14] The PD-L1 gene promoter region has a response element to IRF-1, the interferon regulatory factor.[15] Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.[16]

On macrophages and monocytes

PD-L1 is notably expressed on macrophages. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cells or a combination of LPS and interferon-gamma) greatly upregulate PD-L1.[17] Alternatively, macrophages activated by IL-4 (alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by STAT1-deficient knock-out mice that STAT1 is mostly responsible for upregulation of PD-L1 on macrophages by LPS or interferon-gamma, but is not at all responsible for its constitutive expression before activation in these mice. It was also shown that PD-L1 is constituvely expressed on mouse Ly6Clo nonclassical monocytes in steady state. [18]

Role of microRNAs

Resting human cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by microRNA miR-513.[19] Upon treatment with interferon-gamma, miR-513 was down-regulated, thereby lifting suppression of PD-L1 protein. In this way, interferon-gamma can induce PD-L1 protein expression by inhibiting gene-mediated suppression of mRNA translation. Whereas the Epstein-Barr viral (EBV) latent membrane protein-1 (LMP1) is a known potent inducer of PD-L1, the EBV miRNA miR-BamH1 fragment H rightward open reading frame 1 (BHRF1) 2-5p has been shown to regulate LMP1 induced PD-L1 expression.[20]

Epigenetic regulation

PD-L1 promoter DNA methylation may predict survival in some cancers after surgery.[21]

Clinical significance

Cancer
Micrograph showing a PD-L1 positive lung adenocarcinoma. PD-L1 immunostain.

It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.[22] Many PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.[23] Clinically available examples include Durvalumab, pembrolizumab, atezolizumab and avelumab.[24] In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1. [25]

Listeria monocytogenes

In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells).[26] This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.

Autoimmunity

The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).[27]

In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus (SLE). Studying isolated PBMC from healthy children, immature myeloid dendritic cells and monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5-day time course, expressing this protein only during disease remissions.[28] This may be one mechanism whereby peripheral tolerance is lost in SLE.

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See also

References
  1. GRCh38: Ensembl release 89: ENSG00000120217 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000016496 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: CD274 CD274 molecule".
  6. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (July 2004). "SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation". Journal of Immunology. 173 (2): 945–54. doi:10.4049/jimmunol.173.2.945. PMID 15240681.
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