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PMID: 21960736 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Review

The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion.

Journal of biomedicine & biotechnology ·Vol. 2011 ·2011-00-00 ·Pages 451694

Hofmeyer KA, Jeon H, Zang X

Abstract

Cytotoxic CD8 T lymphocytes (CTLs) play a pivotal role in the control of infection. Activated CTLs, however, often lose effector function during chronic infection. PD-1 receptor and its ligand PD-L1 of the B7/CD28 family function as a T cell coinhibitory pathway and are emerging as major regulators converting effector CTLs into exhausted CTLs during chronic infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and other pathogens capable of establishing chronic infections. Importantly, blockade of the PD-1/PD-L1 pathway is able to restore functional capabilities to exhausted CTLs and early clinical trials have shown promise. Further research will reveal how chronic infection induces upregulation of PD-1 on CTLs and PD-L1 on antigen-presenting cells and other tissue cells and how the PD-1/PD-L1 interaction promotes CTLs exhaustion, which is crucial for developing effective prophylactic and therapeutic vaccination against chronic infections.

MeSH Terms
Animals Antigen-Presenting Cells/metabolism B7-H1 Antigen/genetics,metabolism CD28 Antigens/metabolism CD8-Positive T-Lymphocytes/immunology Chronic Disease Humans Infections/immunology,microbiology Liver/immunology,metabolism Metabolic Networks and Pathways Mice Programmed Cell Death 1 Receptor/genetics,metabolism T-Lymphocytes, Cytotoxic/immunology
Chemicals
B7-H1 Antigen CD28 Antigens Programmed Cell Death 1 Receptor
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Hofmeyer Kimberly A
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Jeon Hyungjun
Zang Xingxing
References (78)
78 references, click to expand
  1. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade.
    PLoS Pathog. 2009 Feb;5(2):e1000313 PMID: 19247441
  2. Viral immune evasion due to persistence of activated T cells without effector function.
    J Exp Med. 1998 Dec 21;188(12):2205-13 PMID: 9858507
  3. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.
    Immunity. 1999 Aug;11(2):141-51 PMID: 10485649
  4. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice.
    Science. 2001 Jan 12;291(5502):319-22 PMID: 11209085
  5. Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity.
    Hepatology. 2007 Mar;45(3):602-13 PMID: 17326154
  6. PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination.
    J Immunol. 2009 Jan 15;182(2):980-7 PMID: 19124741
  7. Restoring function in exhausted CD8 T cells during chronic viral infection.
    Nature. 2006 Feb 9;439(7077):682-7 PMID: 16382236
  8. NFATc1 regulates PD-1 expression upon T cell activation.
    J Immunol. 2008 Oct 1;181(7):4832-9 PMID: 18802087
  9. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.
    Nat Immunol. 2009 Jan;10(1):29-37 PMID: 19043418
  10. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2.
    Eur J Immunol. 2002 Mar;32(3):634-43 PMID: 11857337
  11. Viral escape and T cell exhaustion in hepatitis C virus infection analysed using Class I peptide tetramers.
    Immunol Lett. 2003 Jan 22;85(2):165-71 PMID: 12527224
  12. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection.
    Nat Med. 2010 Apr;16(4):452-9 PMID: 20208540
  13. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade.
    Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15016-21 PMID: 18809920
  14. Dendritic cells in chronic mycobacterial granulomas restrict local anti-bacterial T cell response in a murine model.
    PLoS One. 2010 Jul 06;5(7):e11453 PMID: 20625513
  15. Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages.
    J Immunol. 2004 Jul 15;173(2):1240-8 PMID: 15240716
  16. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.
    J Immunol. 2003 Feb 1;170(3):1257-66 PMID: 12538684
  17. Activation-induced expression of human programmed death-1 gene in T-lymphocytes.
    Exp Cell Res. 1997 Apr 10;232(1):25-8 PMID: 9141617
  18. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes.
    Int Immunol. 1996 May;8(5):765-72 PMID: 8671665
  19. Expression of programmed death 1 ligands by murine T cells and APC.
    J Immunol. 2002 Nov 15;169(10):5538-45 PMID: 12421930
  20. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells.
    J Exp Med. 2001 Apr 2;193(7):839-46 PMID: 11283156
  21. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.
    Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15430-5 PMID: 17878315
  22. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274).
    FEBS Lett. 2006 Feb 6;580(3):755-62 PMID: 16413538
  23. Expression of PD-L1 and PD-L2 on human macrophages is up-regulated by HIV-1 and differentially modulated by IL-10.
    J Leukoc Biol. 2011 Apr;89(4):507-15 PMID: 21097698
  24. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion.
    J Virol. 2006 Nov;80(22):11398-403 PMID: 16956940
  25. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver.
    J Immunol. 2007 Mar 1;178(5):2714-20 PMID: 17312113
  26. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.
    EMBO J. 1992 Nov;11(11):3887-95 PMID: 1396582
  27. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
    J Exp Med. 2000 Oct 2;192(7):1027-34 PMID: 11015443
  28. B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections.
    PLoS Pathog. 2009 May;5(5):e1000431 PMID: 19436710
  29. Expression of programmed-death receptor ligands 1 and 2 may contribute to the poor stimulatory potential of murine immature dendritic cells.
    Immunobiology. 2007;212(3):159-65 PMID: 17412283
  30. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
    Nat Med. 2010 Oct;16(10):1147-51 PMID: 20890291
  31. Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection.
    J Virol. 2009 May;83(9):4386-94 PMID: 19211743
  32. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients.
    Mol Immunol. 2008 Feb;45(4):963-70 PMID: 17868872
  33. 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 U S A. 2001 Nov 20;98(24):13866-71 PMID: 11698646
  34. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.
    J Virol. 2007 Apr;81(8):4215-25 PMID: 17287266
  35. B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infection.
    Eur J Immunol. 2008 Nov;38(11):3226-36 PMID: 18924219
  36. PD-1 inhibits antiviral immunity at the effector phase in the liver.
    J Exp Med. 2003 Jul 7;198(1):39-50 PMID: 12847136
  37. Level of herpes simplex virus type 1 latency correlates with severity of corneal scarring and exhaustion of CD8+ T cells in trigeminal ganglia of latently infected mice.
    J Virol. 2009 Mar;83(5):2246-54 PMID: 19091870
  38. Molecular signature of CD8+ T cell exhaustion during chronic viral infection.
    Immunity. 2007 Oct;27(4):670-84 PMID: 17950003
  39. The B7 family and cancer therapy: costimulation and coinhibition.
    Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5271-9 PMID: 17875755
  40. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
    Nature. 2006 Sep 21;443(7109):350-4 PMID: 16921384
  41. Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques.
    J Clin Invest. 2010 Nov;120(11):3878-90 PMID: 20972331
  42. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
    Nat Med. 2006 Oct;12(10):1198-202 PMID: 16917489
  43. Institute of Medicine recommendations for the prevention and control of hepatitis B and C.
    Hepatology. 2010 Mar;51(3):729-33 PMID: 20186842
  44. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.
    Immunity. 2007 Jul;27(1):111-22 PMID: 17629517
  45. Enhancing SIV-specific immunity in vivo by PD-1 blockade.
    Nature. 2009 Mar 12;458(7235):206-10 PMID: 19078956
  46. PD-L2+ dendritic cells and PD-1+ CD4+ T cells in schistosomiasis correlate with morbidity.
    Parasite Immunol. 2005 Jan-Feb;27(1-2):45-53 PMID: 15813722
  47. Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development.
    Infect Immun. 2007 Feb;75(2):810-9 PMID: 17101659
  48. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction.
    J Immunol. 2007 Aug 1;179(3):1979-87 PMID: 17641065
  49. SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection.
    Blood. 2007 Aug 1;110(3):928-36 PMID: 17440051
  50. The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1.
    J Virol. 2011 May;85(9):4184-97 PMID: 21307196
  51. Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis.
    Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13402-7 PMID: 20624978
  52. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors.
    Blood. 2007 Jun 1;109(11):4671-8 PMID: 17272504
  53. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes.
    J Exp Med. 1998 May 4;187(9):1383-93 PMID: 9565631
  54. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms.
    Mol Cell Biol. 2005 Nov;25(21):9543-53 PMID: 16227604
  55. 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. 2008 May 15;14(10):3044-51 PMID: 18483370
  56. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection.
    J Exp Med. 2008 Mar 17;205(3):543-55 PMID: 18332181
  57. 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. 2004 Jul 15;173(2):945-54 PMID: 15240681
  58. Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection.
    J Exp Med. 2002 May 6;195(9):1089-101 PMID: 11994415
  59. 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. 2007 Jun;81(11):5819-28 PMID: 17376899
  60. Immunization with different viral antigens alters the pattern of T cell exhaustion and latency in herpes simplex virus type 1-infected mice.
    J Virol. 2010 Dec;84(23):12315-24 PMID: 20861248
  61. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.
    Nat Immunol. 2009 Nov;10(11):1185-92 PMID: 19783989
  62. Enhancement of vaccine-induced primary and memory CD8(+) T-cell responses by soluble PD-1.
    J Immunother. 2011 Apr;34(3):297-306 PMID: 21389868
  63. Premature terminal exhaustion of Friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors.
    J Immunol. 2010 May 1;184(9):4696-707 PMID: 20351188
  64. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5336-41 PMID: 12697896
  65. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.
    Nat Med. 1999 Dec;5(12):1365-9 PMID: 10581077
  66. Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade.
    Proc Natl Acad Sci U S A. 2011 May 31;108(22):9196-201 PMID: 21576466
  67. B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression.
    Blood. 2003 Apr 1;101(7):2514-20 PMID: 12468426
  68. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.
    J Immunol. 2011 Feb 1;186(3):1598-607 PMID: 21172867
  69. PD-L2 is a second ligand for PD-1 and inhibits T cell activation.
    Nat Immunol. 2001 Mar;2(3):261-8 PMID: 11224527
  70. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.
    J Exp Med. 2009 Dec 21;206(13):3015-29 PMID: 20008522
  71. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection.
    Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20428-33 PMID: 19075244
  72. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection.
    Nat Immunol. 2011 May 29;12(7):663-71 PMID: 21623380
  73. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection.
    J Immunol. 2006 Mar 1;176(5):3000-9 PMID: 16493058
  74. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV.
    J Clin Invest. 2009 Mar;119(3):551-64 PMID: 19229109
  75. Early CD4(+) T cell help prevents partial CD8(+) T cell exhaustion and promotes maintenance of Herpes Simplex Virus 1 latency.
    J Immunol. 2010 Jan 1;184(1):277-86 PMID: 19949087
  76. Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction.
    J Virol. 2007 Sep;81(17):9249-58 PMID: 17567698
  77. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta.
    FEBS Lett. 2004 Sep 10;574(1-3):37-41 PMID: 15358536
  78. Expression of CD25(high) regulatory T cells and PD-1 in gastric infiltrating CD4(+) T lymphocytes in patients with Helicobacter pylori infection.
    Clin Vaccine Immunol. 2011 Jul;18(7):1198-201 PMID: 21562113
Article Info
Journal
Journal of biomedicine & biotechnology
Abbr.
J Biomed Biotechnol
ISSN
1110-7251
DOI
10.1155/2011/451694
Published
2011-00-00
Epub
2011-00-25
Pages
451694
Language
English
Region
United States
NLM ID
101135740
PMCID
PMC3180079
Subset
IM
Grants
NIDDK NIH HHS · T32 DK007513 · United States
NIDDK NIH HHS · P60DK020541 · United States
NIDDK NIH HHS · DP2 DK083076 · United States
NCI NIH HHS · P30 CA013330 · United States
NCI NIH HHS · P30CA013330 · United States
NIDDK NIH HHS · T32DK007513 · United States
NIDDK NIH HHS · P60 DK020541 · United States
NIDDK NIH HHS · DP2DK083076 · United States
External Links
PubMed source DOI: 10.1155/2011/451694 PMC Full Text
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