View source for PD-L1

{{Infobox_gene}}

'''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]].<ref>{{cite web | title = Entrez Gene: CD274 CD274 molecule| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29126| accessdate = }}</ref>

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 [[immune system]] during particular events such as pregnancy, tissue [[allograft]]s, autoimmune disease and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens that are associated with exogenous or endogenous danger signals, which triggers a proliferation of [[antigen]]-specific [[cytotoxic T cell|CD8+ T cells]] and/or CD4+ helper cells. The binding of PD-L1 to PD-1 or B7.1 transmits an inhibitory signal that 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]].<ref name="pmid15240681">{{cite journal | vauthors = Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL | title = 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 = Journal of Immunology | volume = 173 | issue = 2 | pages = 945–54 | date = July 2004 | pmid = 15240681 | doi = 10.4049/jimmunol.173.2.945 }}</ref>

== 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<ref>{{cite journal | vauthors = Dong H, Zhu G, Tamada K, Chen L | title = B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion | journal = Nature Medicine | volume = 5 | issue = 12 | pages = 1365–9 | date = December 1999 | pmid = 10581077 | doi = 10.1038/70932 | url = https://www.ncbi.nlm.nih.gov/pubmed/?term=10581077 }}</ref> 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.<ref>{{cite journal | vauthors = Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L | title = Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion | journal = Nature Medicine | volume = 8 | issue = 8 | pages = 793–800 | date = August 2002 | pmid = 12091876 | doi = 10.1038/nm730 }}</ref> 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 <ref>{{cite journal | vauthors = Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggren R, Hemminki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W | title = Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity | journal = Nature Medicine | volume = 9 | issue = 5 | pages = 562-7 | date = May 2003 | pmid = 12704383 | doi = 10.1038/nm863 }}</ref>

==Binding==
[[Image:B7 family ligands and CD28 family receptors.JPG|upright=1.25|left|thumb|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]] K<sub>d</sub>, is 770nM. PD-L1 also has an appreciable affinity for the costimulatory molecule [[CD80]] (B7-1), but not [[CD86]] (B7-2).<ref name="pmid18585785">{{cite journal | vauthors = Butte MJ, Peña-Cruz V, Kim MJ, Freeman GJ, Sharpe AH | title = Interaction of human PD-L1 and B7-1 | journal = Molecular Immunology | volume = 45 | issue = 13 | pages = 3567–72 | date = August 2008 | pmid = 18585785 | pmc = 3764616 | doi = 10.1016/j.molimm.2008.05.014 }}</ref> 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 [[PDCD1LG2|PD-L2]] has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger K<sub>d</sub> 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.<ref>{{cite journal | vauthors = Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP | title = Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection | journal = Nature Medicine | volume = 16 | issue = 4 | pages = 452–9 | date = April 2010 | pmid = 20208540 | pmc = 4229134 | doi = 10.1038/nm.2106 }}</ref>

==Signaling==
Engagement of PD-L1 with its receptor [[PD-1]] on T cells delivers a signal that inhibits [[T cell receptor|TCR]]-mediated activation of [[Interleukin 2|IL-2]] production and T cell proliferation. The mechanism involves inhibition of [[ZAP-70|ZAP70]] phosphorylation and its association with [[CD247|CD3ζ]].<ref name="pmid15358536">{{cite journal | vauthors = Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D | title = PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta | journal = FEBS Letters | volume = 574 | issue = 1-3 | pages = 37–41 | date = September 2004 | pmid = 15358536 | pmc =  | doi = 10.1016/j.febslet.2004.07.083 }}</ref> PD-1 signaling attenuates [[PRKCQ|PKC-θ]] activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors [[NF-κB]] and [[AP-1 transcription factor|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.<ref name="pmid21739608">{{cite journal | vauthors = Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D | title = PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells | journal = EMBO Molecular Medicine | volume = 3 | issue = 10 | pages = 581–92 | date = October 2011 | pmid = 21739608 | pmc = 3191120 | doi = 10.1002/emmm.201100165 }}</ref>

== Regulation ==
===By interferons===
Upon [[Interferon-gamma|IFN-γ]] stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells.<ref name="pmid17414316">{{cite journal | vauthors = Flies DB, Chen L | title = The new B7s: playing a pivotal role in tumor immunity | journal = Journal of Immunotherapy | volume = 30 | issue = 3 | pages = 251–60 | date = April 2007 | pmid = 17414316 | pmc =  | doi = 10.1097/CJI.0b013e31802e085a }}</ref> The PD-L1 gene promoter region has a response element to [[IRF1|IRF-1]], the interferon regulatory factor.<ref name="pmid16413538">{{cite journal | vauthors = Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S, Chen L, Choi IH | title = Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274) | journal = FEBS Letters | volume = 580 | issue = 3 | pages = 755–62 | date = February 2006 | pmid = 16413538 | pmc =  | doi = 10.1016/j.febslet.2005.12.093 }}</ref> [[Interferon type I|Type I interferons]] can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.<ref name="pmid12421930">{{cite journal | vauthors = Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H | title = Expression of programmed death 1 ligands by murine T cells and APC | journal = Journal of Immunology | volume = 169 | issue = 10 | pages = 5538–45 | date = November 2002 | pmid = 12421930 | pmc =  | doi = 10.4049/jimmunol.169.10.5538 }}</ref>

===On macrophages===
PD-L1 is notably expressed on [[macrophage]]s. In the mouse, it has been shown that classically activated macrophages (induced by type I [[T helper cell|helper T cell]]s or a combination of [[lipopolysaccharide|LPS]] and [[interferon-gamma]]) greatly upregulate PD-L1.<ref name="pmid12697896">{{cite journal | vauthors = Loke P, Allison JP | title = PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 9 | pages = 5336–41 | date = April 2003 | pmid = 12697896 | pmc = 154346 | doi = 10.1073/pnas.0931259100 }}</ref> Alternatively, macrophages activated by [[Interleukin 4|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.

===Role of microRNAs===
Resting human [[cholangiocyte]]s express PD-L1 mRNA, but not the protein, due to translational suppression by [[microRNA]] miR-513.<ref name="pmid19155478">{{cite journal | vauthors = Gong AY, Zhou R, Hu G, Li X, Splinter PL, O'Hara SP, LaRusso NF, Soukup GA, Dong H, Chen XM | title = MicroRNA-513 regulates B7-H1 translation and is involved in IFN-gamma-induced B7-H1 expression in cholangiocytes | journal = Journal of Immunology | volume = 182 | issue = 3 | pages = 1325–33 | date = February 2009 | pmid = 19155478 | pmc = 2652126 | doi = 10.4049/jimmunol.182.3.1325 }}</ref> 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.

===Epigenetic regulation===
PD-L1 promoter DNA methylation may predict survival in some cancers after surgery.<ref>{{cite journal | vauthors = Gevensleben H, Holmes EE, Goltz D, Dietrich J, Sailer V, Ellinger J, Dietrich D, Kristiansen G | title = PD-L1 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy | journal = Oncotarget | volume = 7 | issue = 48 | pages = 79943–79955 | date = November 2016 | pmid = 27835597 | pmc = 5346762 | doi = 10.18632/oncotarget.13161 }}</ref>

== Clinical significance ==
=== Cancer ===
[[Image:PD-L1_positive_lung_adenocarcinoma_--_high_mag.jpg|right|thumb|upright=.85|[[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.<ref name="pmid15569934">{{cite journal | vauthors = Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED | title = Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 49 | pages = 17174–9 | date = December 2004 | pmid = 15569934 | pmc = 534606 | doi = 10.1073/pnas.0406351101 }}</ref>
Many [[PD-L1 Inhibitor|PD-L1 inhibitors]] are in development as immuno-oncology therapies and are showing good results in clinical trials.<ref name=" pmid = 24217091">{{cite journal | vauthors = Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL | title = Programmed death ligand-1 expression in non-small cell lung cancer | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 94 | issue = 1 | pages = 107–16 | date = January 2014 | pmid = 24217091 | doi = 10.1038/labinvest.2013.130 | url = http://www.nature.com/labinvest/journal/v94/n1/full/labinvest2013130a.html }}</ref> Clinically available examples include [[Durvalumab]], [[atezolizumab]] and [[avelumab]].<ref>{{Cite web|url=https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html|title=Immune checkpoint inhibitors to treat cancer|website=www.cancer.org|access-date=2017-03-27}}</ref>
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.
<ref>{{cite journal|last1=Vlahopoulos|first1=SA|title= Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode.|journal= Cancer biology & medicine|date=15 August 2017|pmid= 28884042|doi= 10.20892/j.issn.2095-3941.2017.0029|volume=14|pages=254–270|pmc=5570602}}</ref>

=== ''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).<ref name="pmid17971153">{{cite journal | vauthors = Seo SK, Jeong HY, Park SG, Lee SW, Choi IW, Chen L, Choi I | title = Blockade of endogenous B7-H1 suppresses antibacterial protection after primary Listeria monocytogenes infection | journal = Immunology | volume = 123 | issue = 1 | pages = 90–9 | date = January 2008 | pmid = 17971153 | pmc = 2433284 | doi = 10.1111/j.1365-2567.2007.02708.x }}</ref> 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).<ref name="pmid12847137 ">{{cite journal | vauthors = Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H, Sayegh MH | title = The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice | journal = The Journal of Experimental Medicine | volume = 198 | issue = 1 | pages = 63–9 | date = July 2003 | pmid = 12847137 | pmc = 2196083 | doi = 10.1084/jem.20022125 }}</ref>

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 [[dendritic cell|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.<ref name="pmid18650228 ">{{cite journal | vauthors = Mozaffarian N, Wiedeman AE, Stevens AM | title = Active systemic lupus erythematosus is associated with failure of antigen-presenting cells to express programmed death ligand-1 | journal = Rheumatology | volume = 47 | issue = 9 | pages = 1335–41 | date = September 2008 | pmid = 18650228 | pmc = 2722808 | doi = 10.1093/rheumatology/ken256 }}</ref> This may be one mechanism whereby peripheral tolerance is lost in SLE.

== See also ==
* [[Cluster of differentiation]]
* [[Co-stimulation]]
* [[Immune tolerance]]

== References ==
{{reflist|32em}}

== External links ==
* {{MeshName|CD274+protein,+human}}

{{Clusters of differentiation}}

{{B7 Family}}

[[Category:Clusters of differentiation]]