Rendering based on PDB .
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 allografts, autoimmune disease and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens where there is some accumulation in the lymph nodes or spleen which triggers a proliferation of antigen-specific CD8+ T cell. The formation of PD-1 receptor / PD-L1 ligand complex transmits an inhibitory signal which reduces the proliferation of these CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene Bcl-2.
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. Interestingly, PD-L1 also has an appreciable affinity for the costimulatory molecule CD80 (B7-1), but not CD86 (B7-2). 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-L1, up-regulated on activated CD4 T-cells, can bind to PD-1 expressed on monocytes and induces IL-10 production by the latter.
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. 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.
Upon IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells. The PD-L1 gene promoter region has a response element to IRF-1, the interferon regulatory factor. Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.
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. 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.
Role of MicroRNAs
Resting human cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by microRNA miR-513. 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.
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. Ovarian cancer patients with higher expression of PD-L1 had a significantly poorer prognosis than those with lower expression. PD-L1 expression correlated inversely with intraepithelial CD8+ T-lymphocyte count, suggesting that PD-L1 on tumor cells may suppress antitumor CD8+ T cells. This has encouraged development of PD-L1 inhibitors which As of April 2013[update] have started clinical trials.
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). This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.
The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity in that they exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to have precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).
In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus. 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. This may be one mechanism whereby peripheral tolerance is lost in SLE.
- "Entrez Gene: CD274 CD274 molecule".
- 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. PMID 15240681.
- Butte MJ, Peña-Cruz V, Kim MJ, Freeman GJ, Sharpe AH (August 2008). "Interaction of human PD-L1 and B7-1". Mol Immunol. 45 (13): 3567–72. doi:10.1016/j.molimm.2008.05.014. PMID 18585785.
- Elias A. Said et al. 2009, PD-1 Induced IL10 Production by Monocytes Impairs T-cell Activation in a Reversible Fashion" Nature Medicine 2010; 452-9.
- Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D. (September 2004). "PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta.". FEBS Lett. 574 (1-3): 37–41. doi:10.1016/j.febslet.2004.07.083. PMID 15358536.
- Flies DB, Chen L (April 2007). "The new B7s: playing a pivotal role in tumor immunity". J Immunother. 30 (3): 251–60. doi:10.1097/CJI.0b013e31802e085a. PMID 17414316.
- Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S, Chen L, Choi IH. (February 2006). "Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274)". FEBS Lett. 580 (3): 755–62. doi:10.1016/j.febslet.2005.12.093. PMID 16413538.
- Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H (November 2002). "Expression of programmed death 1 ligands by murine T cells and APC.". Journal of Immunology 169 (10): 5538–45. PMID 12421930.
- Loke P, Allison JP (April 2003). "PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5336–41. doi:10.1073/pnas.0931259100. PMC 154346. PMID 12697896.
- Gong AY, Zhou R, Hu G, Li X, Splinter PL, O'Hara SP, LaRusso NF, Soukup GA, Dong H, Chen XM (February 2009). "MicroRNA-513 regulates B7-H1 translation and is involved in IFN-gamma-induced B7-H1 expression in cholangiocytes". Journal of Immunology 182 (3): 1325–33. PMC 2652126. PMID 19155478.
- 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 (December 2004). "Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target". Proc Natl Acad Sci USA 101 (49): 17174–9. doi:10.1073/pnas.0406351101. PMC 534606. PMID 15569934.
- Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S. (February 2007). "Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer". Proc Natl Acad Sci USA 104 (9): 3360–5. doi:10.1073/pnas.0611533104. PMC 1805580. PMID 17360651.
- Immune Therapy Safe in Early Trial. April 2012
- Seo SK, Jeong HY, Park SG, Lee SW, Choi IW, Chen L, Choi I (January 2008). "Blockade of endogenous B7-H1 suppresses antibacterial protection after primary Listeria monocytogenes infection". Immunology 123 (1): 90–9. doi:10.1111/j.1365-2567.2007.02708.x. PMC 2433284. PMID 17971153.
- Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H Jr, Sayegh MH (July 2003). "The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice". J Exp Med. 198 (1): 63–9. doi:10.1084/jem.20022125. PMC 2196083. PMID 12847137.
- Mozaffarian N, Wiedeman AE, Stevens AM (July 2008). "Active systemic lupus erythematosus is associated with failure of antigen-presenting cells to express programmed death ligand-1". Rheumatology (Oxford) 47 (9): 1335–41. doi:10.1093/rheumatology/ken256. PMC 2722808. PMID 18650228.
- Tamura H, Ogata K, Dong H, Chen L (2004). "Immunology of B7-H1 and its roles in human diseases.". Int. J. Hematol. 78 (4): 321–8. doi:10.1007/BF02983556. PMID 14686489.
- Dong H, Zhu G, Tamada K, Chen L (1999). "B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.". Nat. Med. 5 (12): 1365–9. doi:10.1038/70932. PMID 10581077.
- Freeman GJ, Long AJ, Iwai Y, et al. (2000). "Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.". J. Exp. Med. 192 (7): 1027–34. doi:10.1084/jem.192.7.1027. PMC 2193311. PMID 11015443.
- Dong H, Strome SE, Salomao DR, et al. (2002). "Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.". Nat. Med. 8 (8): 793–800. doi:10.1038/nm730. PMID 12091876.
- Mazanet MM, Hughes CC (2002). "B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis.". Journal of Immunology 169 (7): 3581–8. PMID 12244148.
- Trabattoni D, Saresella M, Biasin M, et al. (2003). "B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression.". Blood 101 (7): 2514–20. doi:10.1182/blood-2002-10-3065. PMID 12468426.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Brown JA, Dorfman DM, Ma FR, et al. (2003). "Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.". Journal of Immunology 170 (3): 1257–66. PMID 12538684.
- Petroff MG, Chen L, Phillips TA, et al. (2003). "B7 family molecules are favorably positioned at the human maternal-fetal interface.". Biol. Reprod. 68 (5): 1496–504. doi:10.1095/biolreprod.102.010058. PMID 12606489.
- Selenko-Gebauer N, Majdic O, Szekeres A, et al. (2003). "B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy.". Journal of Immunology 170 (7): 3637–44. PMID 12646628.
- Curiel TJ, Wei S, Dong H, et al. (2003). "Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity.". Nat. Med. 9 (5): 562–7. doi:10.1038/nm863. PMID 12704383.
- Wang S, Bajorath J, Flies DB, et al. (2003). "Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction.". J. Exp. Med. 197 (9): 1083–91. doi:10.1084/jem.20021752. PMC 2193977. PMID 12719480.
- Chen XL, Cao XD, Kang AJ, et al. (2003). "In situ expression and significance of B7 costimulatory molecules within tissues of human gastric carcinoma.". World J. Gastroenterol. 9 (6): 1370–3. PMID 12800259.
- Youngnak P, Kozono Y, Kozono H, et al. (2003). "Differential binding properties of B7-H1 and B7-DC to programmed death-1.". Biochem. Biophys. Res. Commun. 307 (3): 672–7. doi:10.1016/S0006-291X(03)01257-9. PMID 12893276.
- Wiendl H, Mitsdoerffer M, Schneider D, et al. (2003). "Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies.". FASEB J. 17 (13): 1892–4. doi:10.1096/fj.03-0039fje. PMID 12923066.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Nakazawa A, Dotan I, Brimnes J, et al. (2004). "The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells.". Gastroenterology 126 (5): 1347–57. doi:10.1053/j.gastro.2004.02.004. PMID 15131796.
- Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9.". Nature 429 (6990): 369–74. doi:10.1038/nature02465. PMC 2734081. PMID 15164053.
- Konishi J, Yamazaki K, Azuma M, et al. (2005). "B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression.". Clin. Cancer Res. 10 (15): 5094–100. doi:10.1158/1078-0432.CCR-04-0428. PMID 15297412.
Chimnitz, JM. (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. The journal of immunology. 173 (1), 945-954.