View source for Biology:PD-L1

{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox_gene}}

'''Programmed death-ligand 1''' (PD-L1) also known as '''cluster of differentiation 274''' (CD274) or '''B7 homolog 1''' (B7-H1) is a [[Biology:Protein|protein]] that in humans is encoded by the ''CD274'' [[Biology:Gene|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}}</ref>

Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 [[Biology:Transmembrane protein|transmembrane protein]] that has been speculated to play a major role in suppressing the [[Biology:Adaptive immune system|adaptive]] arm of immune systems during particular events such as [[Medicine:Pregnancy|pregnancy]], tissue allografts, [[Medicine:Autoimmune disease|autoimmune disease]] and other disease states such as [[Medicine:Hepatitis|hepatitis]]. Normally the adaptive immune system reacts to [[Biology:Antigen|antigen]]s that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of  [[Biology:Antigen|antigen]]-specific [[Biology:Cytotoxic T cell|CD8+ T cells]] and/or [[Biology:T helper cell|CD4+ helper cells]] is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule [[Biology:Programmed cell death protein 1|PD-1]] transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or [[Biology:PTPN11|SHP-2]]) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM).<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 = 945–954 | date = July 2004 | pmid = 15240681 | doi = 10.4049/jimmunol.173.2.945 | doi-access = free }}</ref> This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing [[Biology:Apoptosis|apoptosis]] in regulatory T cells (anti-inflammatory, suppressive T cells) – further mediated by a lower regulation of the gene [[Biology:Bcl-2|Bcl-2]].{{citation needed|date=February 2019}}

== History ==
PD-L1 also known as B7-H1 was characterized at the Mayo Clinic in 1999 as an immune regulatory molecule.<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 = 1365–1369 | date = December 1999 | pmid = 10581077 | doi = 10.1038/70932 | s2cid = 21397460 }}</ref> 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 | display-authors = 6 | 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 | s2cid = 27694471 }}</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 | display-authors = 6 | title = Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity | journal = Nature Medicine | volume = 9 | issue = 5 | pages = 562–567 | date = May 2003 | pmid = 12704383 | doi = 10.1038/nm863 | s2cid = 12499214 }}</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 [[Chemistry:Dissociation constant|dissociation constant]] K<sub>d</sub>, is 770&nbsp;nM. PD-L1 also has an appreciable affinity for the costimulatory molecule [[Biology:CD80|CD80]] (B7-1), but not [[Biology:CD86|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 = 3567–3572 | date = August 2008 | pmid = 18585785 | pmc = 3764616 | doi = 10.1016/j.molimm.2008.05.014 }}</ref> CD80's affinity for PD-L1, 1.4&nbsp;µM, is intermediate between its affinity for [[Biology:CD28|CD28]] and [[Biology:CTLA-4|CTLA-4]] (4.0&nbsp;µM and 400&nbsp;nM, respectively). The related molecule [[Biology: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 140&nbsp;nM). 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 | display-authors = 6 | 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 = 452–459 | 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 TCR-mediated activation of [[Biology:Interleukin 2|IL-2]] production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its association with [[Biology: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 | display-authors = 6 | 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 | doi = 10.1016/j.febslet.2004.07.083 | s2cid = 85034305 }}</ref> PD-1 signaling attenuates [[Biology:PRKCQ|PKC-θ]] activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors [[Biology:NF-κB|NF-κB]] and [[Biology: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 = 581–592 | date = October 2011 | pmid = 21739608 | pmc = 3191120 | doi = 10.1002/emmm.201100165 }}</ref>

== 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.<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 = 251–260 | date = April 2007 | pmid = 17414316 | doi = 10.1097/CJI.0b013e31802e085a }}</ref> The PD-L1 gene promoter region has a response element to [[Biology: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 | display-authors = 6 | 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 = 755–762 | date = February 2006 | pmid = 16413538 | doi = 10.1016/j.febslet.2005.12.093 | s2cid = 11169726 | doi-access = free }}</ref> [[Biology: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 | display-authors = 6 | title = Expression of programmed death 1 ligands by murine T cells and APC | journal = Journal of Immunology | volume = 169 | issue = 10 | pages = 5538–5545 | date = November 2002 | pmid = 12421930 | doi = 10.4049/jimmunol.169.10.5538 | doi-access = free }}</ref>

===On macrophages and monocytes===
PD-L1 is notably expressed on [[Biology:Macrophage|macrophage]]s. In the mouse, it has been shown that classically activated macrophages (induced by type I [[Biology:T helper cell|helper T cell]]s or a combination of [[Biology: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 = 5336–5341 | date = April 2003 | pmid = 12697896 | pmc = 154346 | doi = 10.1073/pnas.0931259100 | doi-access = free | bibcode = 2003PNAS..100.5336L }}</ref> Alternatively, macrophages activated by [[Biology:Interleukin 4|IL-4]] (alternative macrophages), ''slightly'' upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by [[Biology:STAT1|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 Ly6C<sup>lo</sup> nonclassical monocytes in steady state.<ref name="pmid31227596">{{cite journal | vauthors = Bianchini M, Duchêne J, Santovito D, Schloss MJ, Evrard M, Winkels H, Aslani M, Mohanta SK, Horckmans M, Blanchet X, Lacy M, von Hundelshausen P, Atzler D, Habenicht A, Gerdes N, Pelisek J, Ng LG, Steffens S, Weber C, Megens RT | display-authors = 6 | title = PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function | journal = Science Immunology | volume = 4 | issue = 36 | pages = eaar3054 | date = June 2019 | pmid = 31227596 | doi = 10.1126/sciimmunol.aar3054 | s2cid = 195259881 | doi-access = free }}</ref>

===Role of microRNAs===
Resting human [[Biology:Cholangiocyte|cholangiocyte]]s express PD-L1 mRNA, but not the protein, due to translational suppression by [[Biology:MicroRNA|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 | display-authors = 6 | 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 = 1325–1333 | 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. 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 [[Biology:Open reading frame|open reading frame]] 1 (BHRF1) 2-5p has been shown to regulate LMP1 induced PD-L1 expression.<ref name="pmid31856276">{{cite journal | vauthors = Cristino AS, Nourse J, West RA, Sabdia MB, Law SC, Gunawardana J, Vari F, Mujaj S, Thillaiyampalam G, Snell C, Gough M, Keane C, Gandhi MK | display-authors = 6 | title = EBV microRNA-BHRF1-2-5p targets the 3'UTR of immune checkpoint ligands PD-L1 and PD-L2 | journal = Blood | volume = 134 | issue = 25 | pages = 2261–2270 | date = December 2019 | pmid = 31856276 | pmc = 6923667 | doi = 10.1182/blood.2019000889 }}</ref>

===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 | display-authors = 6 | 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|Micrograph]] showing a PD-L1 positive lung adenocarcinoma. PD-L1 immunostain.]]
PD-L1 is shown to be highly expressed in a variety of malignancies, particularly lung cancer. In order to anticipate the effectiveness of gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoints, PD-L1 might be employed as a prognostic marker and a target for anti-cancer immunity.<ref>{{cite journal | vauthors = Razaghi A, Mansouri L, Brodin O, Björnstedt M, Lundahl J | title = Soluble PD-L1 Expression After Intravenous Treatment of Cancer Patients With Selenite in Phase I Clinical Trial | language = English | journal = Frontiers in Oncology | volume = 12 | pages = 906134 | date = 2022-06-02 | pmid = 35720000 | pmc = 9203154 | doi = 10.3389/fonc.2022.906134 | doi-access = free }}</ref> i.e. upregulation of PD-L1 may allow cancers to evade the host immune system. For example, 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 | display-authors = 6 | 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 = 17174–17179 | date = December 2004 | pmid = 15569934 | pmc = 534606 | doi = 10.1073/pnas.0406351101 | doi-access = free | bibcode = 2004PNAS..10117174T }}</ref>

Many 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 | display-authors = 6 | 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 = 107–116 | date = January 2014 | pmid = 24217091 | pmc = 6125250 | doi = 10.1038/labinvest.2013.130 }}</ref> Clinically available examples include [[Chemistry:Durvalumab|durvalumab]], [[Chemistry:Atezolizumab|atezolizumab]] and [[Chemistry:Avelumab|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 | vauthors = Vlahopoulos 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 | volume = 14 | issue = 3 | pages = 254–270 | date = August 2017 | pmid = 28884042 | pmc = 5570602 | doi = 10.20892/j.issn.2095-3941.2017.0029 }}</ref> [[Biology:Chimeric antigen receptor T cell|CAR-T]]<ref>{{cite journal | vauthors = Xie YJ, Dougan M, Jailkhani N, Ingram J, Fang T, Kummer L, Momin N, Pishesha N, Rickelt S, Hynes RO, Ploegh H | display-authors = 6 | title = Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 16 | pages = 7624–7631 | date = April 2019 | pmid = 30936321 | pmc = 6475367 | doi = 10.1073/pnas.1817147116 | bibcode = 2019PNAS..116.7624X | doi-access = free }}</ref> and [[Biology:Natural killer cell|NK]] cells<ref>{{cite journal | vauthors = Fabian KP, Padget MR, Donahue RN, Solocinski K, Robbins Y, Allen CT, Lee JH, Rabizadeh S, Soon-Shiong P, Schlom J, Hodge JW | display-authors = 6 | title = PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations | journal = Journal for Immunotherapy of Cancer | volume = 8 | issue = 1 | pages = e000450 | date = May 2020 | pmid = 32439799 | pmc = 7247398 | doi = 10.1136/jitc-2019-000450 }}</ref> targeting PD-L1 are being evaluated for treating cancer.  pSTAT-1 and PDL-1 expressions also strongly correlate in prostate cancer.<ref>{{cite journal | vauthors = Kazan O, Kir G, Culpan M, Cecikoglu GE, Atis G, Yildirim A | title = The association between PI3K, JAK/STAT pathways with the PDL-1 expression in prostate cancer | journal = Andrologia | issue = e14541 | pages = e14541 | date = July 2022 | volume = 54 | pmid = 35880672 | doi = 10.1111/and.14541 | s2cid = 251068796 }}</ref>

Upregulation of PD-L1 on immune cells (especially myeloid cells) can also lead to formation of an immunosuppressive environment in a highly localized manner that also allow the cancer cells to proliferate.<ref>{{cite journal | vauthors = Nirmal AJ, Maliga Z, Vallius T, Quattrochi B, Chen AA, Jacobson CA, Pelletier RJ, Yapp C, Arias-Camison R, Chen YA, Lian CG, Murphy GF, Santagata S, Sorger PK | display-authors = 6 | title = The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution | journal = Cancer Discovery | volume = 12 | issue = 6 | pages = 1518–1541 | date = June 2022 | pmid = 35404441 | pmc = 9167783 | doi = 10.1158/2159-8290.CD-21-1357 | s2cid = 248083925 }}</ref>

PD-L1 analysis in TNBC is essential for selecting patients eligible for immunotherapy. Inter-observer and intra-observer agreement among the pathologists were found to be substantial. Cases around the 1% cut-off value are specifically challenging.<ref>Zaakouk, M.; Van Bockstal, M.; Galant, C.; Callagy, G.; Provenzano, E.; Hunt, R.; D’Arrigo, C.; Badr, N.M.; O’Sullivan, B.; Starczynski, J.; Tanchel, B.; Mir, Y.; Lewis, P.; Shaaban, A.M. Inter- and Intra-Observer Agreement of PD-L1 SP142 Scoring in Breast Carcinoma—A Large Multi-Institutional International Study. Cancers 2023, 15, 1511. https://doi.org/10.3390/cancers15051511</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 = 90–99 | 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 ===
PD-1/PD-L1 interaction is thought to play a role in preventing destructive autoimmunity, especially during inflammatory conditions. The best example is in the stomach, where PD-1 expression protects the [[Biology:Gastrin|gastrin]] expressing G-cells from the immune system during Helicobacter pylori-provoked inflammation.<ref>{{cite journal | vauthors = Mommersteeg MC, Yu BT, van den Bosch TP, von der Thüsen JH, Kuipers EJ, Doukas M, Spaander MC, Peppelenbosch MP, Fuhler GM | title = Constitutive programmed death ligand 1 expression protects gastric G-cells from Helicobacter pylori-induced inflammation | journal = Helicobacter | volume = 27 | issue = 5 | pages = e12917 | date = October 2022 | pmid = 35899973 | doi = 10.1111/hel.12917| pmc = 9542424 }}</ref> But also a variety of pre-clinical studies support the notion that the PD-1/PD-L1 interaction is implicated in autoimmunity. [[Biology:NOD mice|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 | display-authors = 6 | 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 = 63–69 | 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 [[Medicine:Systemic lupus erythematosus|systemic lupus erythematosus]] (SLE). Studying isolated PBMC from healthy children, immature [[Biology: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 = 1335–1341 | 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 ==
* [[Biology:Cluster of differentiation|Cluster of differentiation]]
* [[Biology:Co-stimulation|Co-stimulation]]
* [[Biology:Immune tolerance|Immune tolerance]]

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

== External links ==
* {{MeshName|CD274+protein,+human}}
* {{PDBe-KB2|Q9NZQ7|Programmed cell death 1 ligand 1}}

{{Clusters of differentiation}}

{{B7 Family}}

[[Category:Clusters of differentiation]]

{{Sourceattribution|PD-L1}}