Skip to main content
SpringerLink
Log in
Book cover

Negative Co-Receptors and Ligands pp 17–37Cite as

Role of PD-1 in Regulating T-Cell Immunity

  • Chapter
  • First Online:

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 350))

Abstract

Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed and exert a wider range of immunoregulatory roles in T cells activation and tolerance compared with other CD28 family members. Subsequent studies show that PD-1–PD-L interaction regulates the induction and maintenance of peripheral tolerance and protect tissues from autoimmune attack. PD-1 and its ligands are also involved in attenuating infectious immunity and tumor immunity, and facilitating chronic infection and tumor progression. The biological significance of PD-1 and its ligand suggests the therapeutic potential of manipulation of PD-1 pathway against various human diseases. In this review, we summarize our current understanding of PD-1 and its ligands ranging from discovery to clinical significance.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772

    PubMed  CAS  Google Scholar 

  • 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 (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198:63–69

    PubMed  CAS  Google Scholar 

  • Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687

    PubMed  CAS  Google Scholar 

  • Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 14:3044–3051

    PubMed  CAS  Google Scholar 

  • Bertsias GK, Nakou M, Choulaki C, Raptopoulou A, Papadimitraki E, Goulielmos G, Kritikos H, Sidiropoulos P, Tzardi M, Kardassis D, Mamalaki C, Boumpas DT (2009) Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus. Arthritis Rheum 60:207–218

    PubMed  CAS  Google Scholar 

  • Bishop KD, Harris JE, Mordes JP, Greiner DL, Rossini AA, Czech MP, Phillips NE (2009) Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+) T lymphocytes via an interleukin-2-dependent mechanism. Cell Immunol 256:86–91

    PubMed  CAS  Google Scholar 

  • Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37

    PubMed  CAS  Google Scholar 

  • Blank C, Brown I, Marks R, Nishimura H, Honjo T, Gajewski TF (2003) Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells. J Immunol 171:4574–4581

    PubMed  CAS  Google Scholar 

  • Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF (2004) PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64:1140–1145

    PubMed  CAS  Google Scholar 

  • Blattman JN, Wherry EJ, Ha SJ, van der Most RG, Ahmed R (2009) Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J Virol 83:4386–4394

    PubMed  CAS  Google Scholar 

  • Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R (2006) Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol 80:3532–3540

    PubMed  CAS  Google Scholar 

  • Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, Laccabue D, Zerbini A, Cavalli A, Missale G, Bertoletti A, Ferrari C (2007) Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 81:4215–4225

    PubMed  CAS  Google Scholar 

  • Borkner L, Kaiser A, van de Kasteele W, Andreesen R, Mackensen A, Haanen JB, Schumacher TN, Blank C (2010) RNA interference targeting programmed death receptor-1 improves immune functions of tumor-specific T cells. Cancer Immunol Immunother 59(8):1173–1183

    PubMed  CAS  Google Scholar 

  • Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175

    PubMed  CAS  Google Scholar 

  • Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ (2003) Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170:1257–1266

    PubMed  CAS  Google Scholar 

  • Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–122

    PubMed  CAS  Google Scholar 

  • Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (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. J Immunol 173:945–954

    PubMed  CAS  Google Scholar 

  • Chikuma S, Terawaki S, Hayashi T, Nabeshima R, Yoshida T, Shibayama S, Okazaki T, Honjo T (2009) PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol 182:6682–6689

    PubMed  CAS  Google Scholar 

  • Cho HY, Lee SW, Seo SK, Choi IW, Choi I (2008) Interferon-sensitive response element (ISRE) is mainly responsible for IFN-alpha-induced upregulation of programmed death-1 (PD-1) in macrophages. Biochim Biophys Acta 1779:811–819

    PubMed  CAS  Google Scholar 

  • 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 (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567

    PubMed  CAS  Google Scholar 

  • Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–354

    PubMed  CAS  Google Scholar 

  • Ding H, Wu X, Wu J, Yagita H, He Y, Zhang J, Ren J, Gao W (2006) Delivering PD-1 inhibitory signal concomitant with blocking ICOS co-stimulation suppresses lupus-like syndrome in autoimmune BXSB mice. Clin Immunol 118:258–267

    PubMed  CAS  Google Scholar 

  • 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 5:1365–1369

    PubMed  CAS  Google Scholar 

  • Dong H, Strome SE, Matteson EL, Moder KG, Flies DB, Zhu G, Tamura H, Driscoll CL, Chen L (2003) Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 111:363–370

    PubMed  CAS  Google Scholar 

  • D'Souza M, Fontenot AP, Mack DG, Lozupone C, Dillon S, Meditz A, Wilson CC, Connick E, Palmer BE (2007) Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J Immunol 179:1979–1987

    PubMed  Google Scholar 

  • Eppihimer MJ, Gunn J, Freeman GJ, Greenfield EA, Chernova T, Erickson J, Leonard JP (2002) Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation 9:133–145

    PubMed  CAS  Google Scholar 

  • Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029

    PubMed  CAS  Google Scholar 

  • 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 (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    PubMed  CAS  Google Scholar 

  • Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 203:2223–2227

    PubMed  CAS  Google Scholar 

  • Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR (2007) Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J Virol 81:9249–9258

    PubMed  CAS  Google Scholar 

  • Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, Noelle RJ, Coyle A, Mellor AL, Khoury SJ, Sayegh MH (2005) A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 202:231–237

    PubMed  CAS  Google Scholar 

  • Habicht A, Kewalaramani R, Vu MD, Demirci G, Blazar BR, Sayegh MH, Li XC (2007) Striking dichotomy of PD-L1 and PD-L2 pathways in regulating alloreactive CD4(+) and CD8(+) T cells in vivo. Am J Transplant 7:2683–2692

    PubMed  CAS  Google Scholar 

  • Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (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 104:3360–3365

    PubMed  CAS  Google Scholar 

  • He YF, Zhang GM, Wang XH, Zhang H, Yuan Y, Li D, Feng ZH (2004) Blocking programmed death-1 ligand-PD-1 interactions by local gene therapy results in enhancement of antitumor effect of secondary lymphoid tissue chemokine. J Immunol 173:4919–4928

    PubMed  CAS  Google Scholar 

  • Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116:1757–1766

    PubMed  Google Scholar 

  • Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada K, Chen L (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:1089–1096

    PubMed  CAS  Google Scholar 

  • Hirata S, Senju S, Matsuyoshi H, Fukuma D, Uemura Y, Nishimura Y (2005) Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand. J Immunol 174:1888–1897

    PubMed  CAS  Google Scholar 

  • Holets LM, Hunt JS, Petroff MG (2006) Trophoblast CD274 (B7-H1) is differentially expressed across gestation: influence of oxygen concentration. Biol Reprod 74:352–358

    PubMed  CAS  Google Scholar 

  • Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, Takemori T, Okumura K, Yagita H, Azuma M (2006) B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J Immunol 177:5928–5935

    PubMed  CAS  Google Scholar 

  • Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895

    PubMed  CAS  Google Scholar 

  • Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (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 USA 99:12293–12297

    PubMed  CAS  Google Scholar 

  • Iwai Y, Terawaki S, Honjo T (2005) PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol 17:133–144

    PubMed  CAS  Google Scholar 

  • Kanai T, Totsuka T, Uraushihara K, Makita S, Nakamura T, Koganei K, Fukushima T, Akiba H, Yagita H, Okumura K, Machida U, Iwai H, Azuma M, Chen L, Watanabe M (2003) Blockade of B7-H1 suppresses the development of chronic intestinal inflammation. J Immunol 171:4156–4163

    PubMed  CAS  Google Scholar 

  • Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S, Berical A, Blum J, McMahon C, Reyor LL, Elias N, Kwok WW, McGovern BG, Freeman G, Chung RT, Klenerman P, Lewis-Ximenez L, Walker BD, Allen TM, Kim AY, Lauer GM (2008) High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J Virol 82:3154–3160

    PubMed  CAS  Google Scholar 

  • Keir ME, Latchman YE, Freeman GJ, Sharpe AH (2005) Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol 175:7372–7379

    PubMed  CAS  Google Scholar 

  • Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203:883–895

    PubMed  CAS  Google Scholar 

  • Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704

    PubMed  CAS  Google Scholar 

  • Klenerman P, Hill A (2005) T cells and viral persistence: lessons from diverse infections. Nat Immunol 6:873–879

    PubMed  CAS  Google Scholar 

  • Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, Maurer M, Wiendl H (2005) A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 58:50–57

    PubMed  CAS  Google Scholar 

  • 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 (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

    PubMed  CAS  Google Scholar 

  • Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, Kuchroo VK, Freeman GJ, Sharpe AH (2004) PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA 101:10691–10696

    PubMed  CAS  Google Scholar 

  • Lazar-Molnar E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC (2008) Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci USA 105:10483–10488

    PubMed  CAS  Google Scholar 

  • Lee SH, Lee YA, Woo DH, Song R, Park EK, Ryu MH, Kim YH, Kim KS, Hong SJ, Yoo MC, Yang HI (2006a) Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population. Arthritis Res Ther 8:R163

    PubMed  Google Scholar 

  • Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S, Chen L, Choi IH (2006b) Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FEBS Lett 580:755–762

    PubMed  CAS  Google Scholar 

  • Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, Sharpe AH (2003) Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 33:2706–2716

    PubMed  CAS  Google Scholar 

  • Lin DY, Tanaka Y, Iwasaki M, Gittis AG, Su HP, Mikami B, Okazaki T, Honjo T, Minato N, Garboczi DN (2008) The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci USA 105:3011–3016

    PubMed  CAS  Google Scholar 

  • Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B (2007) Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 110:296–304

    PubMed  CAS  Google Scholar 

  • Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904

    PubMed  CAS  Google Scholar 

  • Matsumoto K, Inoue H, Nakano T, Tsuda M, Yoshiura Y, Fukuyama S, Tsushima F, Hoshino T, Aizawa H, Akiba H, Pardoll D, Hara N, Yagita H, Azuma M, Nakanishi Y (2004) B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol 172:2530–2541

    PubMed  CAS  Google Scholar 

  • Meng Q, Yang P, Li B, Zhou H, Huang X, Zhu L, Ren Y, Kijlstra A (2006) CD4+PD-1+ T cells acting as regulatory cells during the induction of anterior chamber-associated immune deviation. Invest Ophthalmol Vis Sci 47:4444–4452

    PubMed  Google Scholar 

  • Moll M, Kuylenstierna C, Gonzalez VD, Andersson SK, Bosnjak L, Sonnerborg A, Quigley MF, Sandberg JK (2009) Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infection. Eur J Immunol 39:902–911

    PubMed  CAS  Google Scholar 

  • Muthumani K, Choo AY, Shedlock DJ, Laddy DJ, Sundaram SG, Hirao L, Wu L, Thieu KP, Chung CW, Lankaraman KM, Tebas P, Silvestri G, Weiner DB (2008) Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J Virol 82:11536–11544

    PubMed  CAS  Google Scholar 

  • Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 176:2238–2248

    PubMed  CAS  Google Scholar 

  • Nakamoto N, Kaplan DE, Coleclough J, Li Y, Valiga ME, Kaminski M, Shaked A, Olthoff K, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM (2008) Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134:1927–1937

    PubMed  CAS  Google Scholar 

  • Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S (2007) Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56:1173–1182

    PubMed  CAS  Google Scholar 

  • Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST (2003) Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 62:492–497

    PubMed  CAS  Google Scholar 

  • Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, Nakano T, Honjo T (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 8:773–780

    PubMed  CAS  Google Scholar 

  • Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

    PubMed  CAS  Google Scholar 

  • Nishimura H, Honjo T, Minato N (2000) Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 191:891–898

    PubMed  CAS  Google Scholar 

  • Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322

    PubMed  CAS  Google Scholar 

  • Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y (2007) Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 13:2151–2157

    PubMed  CAS  Google Scholar 

  • Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1 regulates PD-1 expression upon T cell activation. J Immunol 181:4832–4839

    PubMed  CAS  Google Scholar 

  • 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 (2005) Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 11:2947–2953

    PubMed  CAS  Google Scholar 

  • Okazaki T, Honjo T (2007) PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19:813–824

    PubMed  CAS  Google Scholar 

  • Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 98:13866–13871

    PubMed  CAS  Google Scholar 

  • Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9:1477–1483

    PubMed  CAS  Google Scholar 

  • Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553

    PubMed  CAS  Google Scholar 

  • Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13:84–88

    PubMed  CAS  Google Scholar 

  • Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, Koup RA (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203:2281–2292

    PubMed  CAS  Google Scholar 

  • Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669

    PubMed  CAS  Google Scholar 

  • Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, Azuma M, Yagita H, Sayegh MH, Khoury SJ (2003) Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 198:71–78

    PubMed  CAS  Google Scholar 

  • Schreiner B, Mitsdoerffer M, Kieseier BC, Chen L, Hartung HP, Weller M, Wiendl H (2004) Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 155:172–182

    PubMed  CAS  Google Scholar 

  • Selenko-Gebauer N, Majdic O, Szekeres A, Hofler G, Guthann E, Korthauer U, Zlabinger G, Steinberger P, Pickl WF, Stockinger H, Knapp W, Stockl J (2003) B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol 170:3637–3644

    PubMed  CAS  Google Scholar 

  • Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D (2004) PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 574:37–41

    PubMed  CAS  Google Scholar 

  • Shin H, Wherry EJ (2007) CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol 19:408–415

    PubMed  CAS  Google Scholar 

  • Sidorenko SP, Clark EA (2003) The dual-function CD150 receptor subfamily: the viral attraction. Nat Immunol 4:19–24

    PubMed  CAS  Google Scholar 

  • Streeck H, Brumme ZL, Anastario M, Cohen KW, Jolin JS, Meier A, Brumme CJ, Rosenberg ES, Alter G, Allen TM, Walker BD, Altfeld M (2008) Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med 5:e100

    PubMed  Google Scholar 

  • Sugita S, Usui Y, Horie S, Futagami Y, Yamada Y, Ma J, Kezuka T, Hamada H, Usui T, Mochizuki M, Yamagami S (2009) Human corneal endothelial cells expressing programmed death-ligand 1 (PD-L1) suppress PD-1+ T helper 1 cells by a contact-dependent mechanism. Invest Ophthalmol Vis Sci 50:263–272

    PubMed  Google Scholar 

  • Terawaki S, Tanaka Y, Nagakura T, Hayashi T, Shibayama S, Muroi K, Okazaki T, Mikami B, Garboczi DN, Honjo T, Minato N (2007) Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function. Int Immunol 19:881–890

    PubMed  CAS  Google Scholar 

  • 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 (2004) Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 101:17174–17179

    PubMed  CAS  Google Scholar 

  • Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12:1198–1202

    PubMed  CAS  Google Scholar 

  • Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H (2001) B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 193:839–846

    PubMed  CAS  Google Scholar 

  • Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, Ferrari C (2006) PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 80:11398–11403

    PubMed  CAS  Google Scholar 

  • Velu V, Kannanganat S, Ibegbu C, Chennareddi L, Villinger F, Freeman GJ, Ahmed R, Amara RR (2007) Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J Virol 81:5819–5828

    PubMed  CAS  Google Scholar 

  • Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ, Ahmed R, Amara RR (2009) Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458:206–210

    PubMed  CAS  Google Scholar 

  • Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T (2005) Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA 102:11823–11828

    PubMed  CAS  Google Scholar 

  • Wang J, Okazaki IM, Yoshida T, Chikuma S, Kato Y, Nakaki F, Hiai H, Honjo T, Okazaki T (2010) PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol 22:443–452

    PubMed  CAS  Google Scholar 

  • Watson MP, George AJ, Larkin DF (2006) Differential effects of costimulatory pathway modulation on corneal allograft survival. Invest Ophthalmol Vis Sci 47:3417–3422

    PubMed  Google Scholar 

  • Wherry EJ, Ahmed R (2004) Memory CD8 T-cell differentiation during viral infection. J Virol 78:5535–5545

    PubMed  CAS  Google Scholar 

  • Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77:4911–4927

    PubMed  CAS  Google Scholar 

  • Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108:19–24

    PubMed  Google Scholar 

  • Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169:5538–5545

    PubMed  CAS  Google Scholar 

  • Yao ZQ, King E, Prayther D, Yin D, Moorman J (2007) T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling. Viral Immunol 20:276–287

    PubMed  CAS  Google Scholar 

  • Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, Nathenson SG, Almo SC (2004) Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20:337–347

    PubMed  CAS  Google Scholar 

  • Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL (2007) PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 37:2405–2410

    PubMed  CAS  Google Scholar 

  • Zhu B, Guleria I, Khosroshahi A, Chitnis T, Imitola J, Azuma M, Yagita H, Sayegh MH, Khoury SJ (2006) Differential role of programmed death-ligand 1 [corrected] and programmed death-ligand 2 [corrected] in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis. J Immunol 176:3480–3489

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Hyun-Tak Jin & Rafi Ahmed

  2. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Hyun-Tak Jin & Rafi Ahmed

  3. Division of Immune Regulation, Institute for Genome Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan

    Taku Okazaki

Authors
  1. Hyun-Tak Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rafi Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taku Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Taku Okazaki .

Editor information

Editors and Affiliations

  1. Emory Vaccine Center &, Yerkes National Primate Research Center, Emory University, Gatewood Rd. 954, Atlanta, 30329, Georgia, USA

    Rafi Ahmed

  2. Fac. Medicine, Dept. Medical Chemistry and Molecular, Kyoto University, Yoshida Konoe-cho, Kyoto, 606-8501, Japan

    Tasuku Honjo

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Jin, HT., Ahmed, R., Okazaki, T. (2010). Role of PD-1 in Regulating T-Cell Immunity. In: Ahmed, R., Honjo, T. (eds) Negative Co-Receptors and Ligands. Current Topics in Microbiology and Immunology, vol 350. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_116

Download citation

Publish with us

Policies and ethics

Search

Navigation