Programmed cell death 1
|Programmed cell death 1|
|RNA expression pattern|
Programmed cell death protein 1 also known as PD-1 is a protein that in humans is encoded by the PDCD1 gene. PDCD1 has also been designated as CD279 (cluster of differentiation 279). This gene encodes a cell surface membrane protein of the immunoglobulin superfamily. This protein is expressed in pro-B cells and is thought to play a role in their differentiation.
Programmed death 1 is a type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.
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. In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion. Reduced T cell proliferation correlated with attenuated IL-2 secretion, which can be rescued by addition of cross-linking anti-CD28 antibodies or exogenous IL-2.
Together, these data suggest that PD-1 negatively regulates T cell responses. 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 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.
As CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecule PD-1 has been independently explored as a target for immunotherapy. The 2C TCR recognizes the peptide SIYRYYGL in the context of H 2kb. 2C CD8 T cells incubated with IFN-γ treated B16 targets expressing SIYRYYGL peptide poorly lyse their targets and secrete low levels of IL-2. However, PD-1 knockout 2C T cells have heightened cytolytic capacity and IL-2 secretion, suggesting that PD-1 negatively regulates anti-tumor CD8 T cell responses. Similarly, P815 mastocytoma, which does not express PD-L1 unless treated with IFN-γ, can be transduced to express PD-L1, resulting in inhibition of in vitro CD8-mediated cytotoxicity and enhanced in vivo tumor growth. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1 Together, these data suggest that expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. 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. Said et al. showed that 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.
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.
One such antibody, nivolumab, produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients. Colon and pancreatic cancer did not have a response.
- Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (Mar 1995). "Structure and chromosomal localization of the human PD-1 gene (PDCD1)". Genomics 23 (3): 704–6. doi:10.1006/geno.1994.1562. PMID 7851902.
- "Entrez Gene: PDCD1 programmed cell death 1".
- Ishida Y, Agata Y, Shibahara K, Honjo T (November 1992). "Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death". EMBO J. 11 (11): 3887–95. PMC 556898. PMID 1396582.
- Blank C, Mackensen A (May 2007). "Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion". Cancer Immunol. Immunother. 56 (5): 739–45. doi:10.1007/s00262-006-0272-1. PMID 17195077.
- Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (May 1996). "Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes". Int. Immunol. 8 (5): 765–72. doi:10.1093/intimm/8.5.765. PMID 8671665.
- Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (October 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.
- Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (March 2001). "PD-L2 is a second ligand for PD-1 and inhibits T cell activation". Nat. Immunol. 2 (3): 261–8. doi:10.1038/85330. PMID 11224527.
- 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". J. Immunol. 169 (10): 5538–45. PMID 12421930.
- Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (September 2002). "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12293–7. doi:10.1073/pnas.192461099. PMC 129438. PMID 12218188.
- Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF (February 2004). "PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells". Cancer Res. 64 (3): 1140–5. doi:10.1158/0008-5472.CAN-03-3259. PMID 14871849.
- Nishimura H, Nose M, Hiai H, Minato N, Honjo T (August 1999). "Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor". Immunity 11 (2): 141–51. doi:10.1016/S1074-7613(00)80089-8. PMID 10485649.
- Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (January 2001). "Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice". Science 291 (5502): 319–22. doi:10.1126/science.291.5502.319. PMID 11209085.
- Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM (March 2002). "PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2". Eur. J. Immunol. 32 (3): 634–43. doi:10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. PMID 11857337.
- Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (February 2006). "Restoring function in exhausted CD8 T cells during chronic viral infection". Nature 439 (7077): 682–7. doi:10.1038/nature04444. PMID 16382236.
- Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y (April 2005). "Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer". Clin. Cancer Res. 11 (8): 2947–53. doi:10.1158/1078-0432.CCR-04-1469. PMID 15837746.
- 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 (April 2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nat. Med. 16 (4): 452–9. doi:10.1038/nm.2106. PMID 20208540.
- Weber J (October 2010). "Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade". Semin. Oncol. 37 (5): 430–9. doi:10.1053/j.seminoncol.2010.09.005. PMID 21074057.
- Topalian SL, et al. (June 2012). "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer". New England Journal of Medicine 366. doi:10.1056/NEJMoa1200690. Lay summary – New York Times.
- Porichis F, Kaufmann DE (March 2012). "Role of PD-1 in HIV pathogenesis and as target for therapy". Curr HIV/AIDS Rep 9 (1): 81–90. doi:10.1007/s11904-011-0106-4. PMID 22198819.
- Vibhakar R, Juan G, Traganos F, et al. (1997). "Activation-induced expression of human programmed death-1 gene in T-lymphocytes.". Exp. Cell Res. 232 (1): 25–8. doi:10.1006/excr.1997.3493. PMID 9141617.
- Finger LR, Pu J, Wasserman R, et al. (1997). "The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors.". Gene 197 (1-2): 177–87. doi:10.1016/S0378-1119(97)00260-6. PMID 9332365.
- Iwai Y, Okazaki T, Nishimura H, et al. (2003). "Microanatomical localization of PD-1 in human tonsils.". Immunol. Lett. 83 (3): 215–20. doi:10.1016/S0165-2478(02)00088-3. PMID 12095712.
- Prokunina L, Castillejo-López C, Oberg F, et al. (2003). "A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.". Nat. Genet. 32 (4): 666–9. doi:10.1038/ng1020. PMID 12402038.
- 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.
- Bennett F, Luxenberg D, Ling V, et al. (2003). "Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.". J. Immunol. 170 (2): 711–8. PMID 12517932.
- 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.
- 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.
- Nielsen C, Hansen D, Husby S, et al. (2004). "Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes.". Tissue Antigens 62 (6): 492–7. doi:10.1046/j.1399-0039.2003.00136.x. PMID 14617032.
- Prokunina L, Gunnarsson I, Sturfelt G, et al. (2004). "The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis.". Arthritis Rheum. 50 (1): 327–8. doi:10.1002/art.11442. PMID 14730631.
- Lin SC, Yen JH, Tsai JJ, et al. (2004). "Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus.". Arthritis Rheum. 50 (3): 770–5. doi:10.1002/art.20040. PMID 15022318.
- Prokunina L, Padyukov L, Bennet A, et al. (2004). "Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope.". Arthritis Rheum. 50 (6): 1770–3. doi:10.1002/art.20280. PMID 15188352.
- Sanghera DK, Manzi S, Bontempo F, et al. (2004). "Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies.". Hum. Genet. 115 (5): 393–8. doi:10.1007/s00439-004-1172-0. PMID 15322919.
- Nielsen C, Laustrup H, Voss A, et al. (2005). "A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients.". Lupus 13 (7): 510–6. doi:10.1191/0961203303lu1052oa. PMID 15352422.
- Johansson M, Arlestig L, Möller B, Rantapää-Dahlqvist S (2005). "Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus.". Arthritis Rheum. 52 (6): 1665–9. doi:10.1002/art.21058. PMID 15934088.
- Nielsen C, Ohm-Laursen L, Barington T, et al. (2005). "Alternative splice variants of the human PD-1 gene.". Cell. Immunol. 235 (2): 109–16. doi:10.1016/j.cellimm.2005.07.007. PMID 16171790.
- Parry RV, Chemnitz JM, Frauwirth KA, et al. (2005). "CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms.". Mol. Cell. Biol. 25 (21): 9543–53. doi:10.1128/MCB.25.21.9543-9553.2005. PMC 1265804. PMID 16227604.
- Kobayashi M, Kawano S, Hatachi S, et al. (2005). "Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren's syndrome.". J. Rheumatol. 32 (11): 2156–63. PMID 16265694.