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Nature Medicine
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Programmed death-1–induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection

Nature Medicinevolume 16, pages452–459 (2010)Cite this article

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Abstract

Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.

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Figure 1: PD-1 expression is upregulated in CD16− and CD16+ monocyte subsets during HIV infection.
Figure 2: PD-1 expression in monocytes is upregulated by TLR ligands of bacterial origin and inflammatory cytokines and correlate with IL-10 concentrations in the blood of viremic subjects.
Figure 3: Specific PD-1 triggering induces IL-10 production by monocytes.
Figure 4: IL-10 production by monocytes from viremic subjects is specifically induced by PD-1–PD-L1 interaction.
Figure 5: IL-10 production induced by PD-1 triggering on monocytes inhibits CD4+ T cell proliferation and cytokine production.
Figure 6: Phosphorylation of STAT-3 by IL-10 produced by PD-1–triggered monocytes and correlation of PD-1, PD-L1 and IL-10R expression in CD4+ T cells.

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References

  1. El-Far, M. et al. T-cell exhaustion in HIV infection.Curr. HIV/AIDS Rep.5, 13–19 (2008).

    Article  Google Scholar 

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

    Article CAS  Google Scholar 

  3. Brenchley, J.M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection.Nat. Med.12, 1365–1371 (2006).

    Article CAS  Google Scholar 

  4. Breen, E.C. et al. Infection with HIV is associated with elevated IL-6 levels and production.J. Immunol.144, 480–484 (1990).

    CAS PubMed  Google Scholar 

  5. Chollet-Martin, S. et al. Comparison of plasma cytokine levels in African patients with HIV-1 and HIV-2 infection.AIDS8, 879–884 (1994).

    Article CAS  Google Scholar 

  6. Ketlinskii, S.A. et al. Tumor necrosis factor-α and interleukin-1β in the blood plasma of patients with HIV infection.Vestn. Ross. Akad. Med. Nauk.9–10, 36–41 (1992).

    Google Scholar 

  7. Norris, P.J. et al. Elevations in IL-10, TNF-α, and IFN-γ from the earliest point of HIV Type 1 infection.AIDS Res. Hum. Retroviruses22, 757–762 (2006).

    Article CAS  Google Scholar 

  8. Salazar-Gonzalez, J.F. et al. Relationship of plasma HIV-RNA levels and levels of TNF-α and immune activation products in HIV infection.Clin. Immunol. Immunopathol.84, 36–45 (1997).

    Article CAS  Google Scholar 

  9. Than, S. et al. Cytokine pattern in relation to disease progression in human immunodeficiency virus–infected children.J. Infect. Dis.175, 47–56 (1997).

    Article CAS  Google Scholar 

  10. Barber, D.L. et al. Restoring function in exhausted CD8+ T cells during chronic viral infection.Nature439, 682–687 (2006).

    Article CAS  Google Scholar 

  11. Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T cell exhaustion and disease progression.Nature443, 350–354 (2006).

    Article CAS  Google Scholar 

  12. Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.Nat. Med.12, 1198–1202 (2006).

    Article CAS  Google Scholar 

  13. Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection.J. Exp. Med.203, 2281–2292 (2006).

    Article CAS  Google Scholar 

  14. Velu, V. et al. Enhancing SIV-specific immunityin vivo by PD-1.blockade.Nature458, 206–210 (2009).

    Article CAS  Google Scholar 

  15. Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistencein vivo.Nat. Med.12, 1301–1309 (2006).

    Article CAS  Google Scholar 

  16. Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade.J. Exp. Med.203, 2461–2472 (2006).

    Article CAS  Google Scholar 

  17. Clerici, M. et al. Human immunodeficiency virus (HIV) phenotype and interleukin-2/ interleukin-10 ratio are associated markers of protection and progression in HIV infection.Blood88, 574–579 (1996).

    CAS PubMed  Google Scholar 

  18. Stylianou, E., Aukrust, P., Kvale, D., Muller, F. & Froland, S.S. IL-10 in HIV infection: increasing serum IL-10 levels with disease progression–down-regulatory effect of potent anti-retroviral therapy.Clin. Exp. Immunol.116, 115–120 (1999).

    Article CAS  Google Scholar 

  19. Orsilles, M.A., Pieri, E., Cooke, P. & Caula, C. IL-2 and IL-10 serum levels in HIV-1–infected patients with or without active antiretroviral therapy.APMIS114, 55–60 (2006).

    Article CAS  Google Scholar 

  20. Clerici, M. et al. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus.J. Clin. Invest.93, 768–775 (1994).

    Article CAS  Google Scholar 

  21. Hagiwara, E., Sacks, T., Leitman-Klinman, S.F. & Klinman, D.M. Effect of HIV infection on the frequency of cytokine-secreting cells in human peripheral blood.AIDS Res. Hum. Retroviruses12, 127–133 (1996).

    Article CAS  Google Scholar 

  22. Kumar, A. et al. Differential production of IL-10 by T cells and monocytes of HIV-infected individuals: association of IL-10 production with CD28-mediated immune responsiveness.Clin. Exp. Immunol.114, 78–86 (1998).

    Article CAS  Google Scholar 

  23. Gröschel, S. et al. TLR-mediated induction of negative regulatory ligands on dendritic cells.J. Mol. Med.86, 443–455 (2008).

    Article  Google Scholar 

  24. Meier, A. et al. Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands.AIDS22, 655–658 (2008).

    Article CAS  Google Scholar 

  25. Keir, M.E., Butte, M.J., Freeman, G.J. & Sharpe, A.H. PD-1 and its ligands in tolerance and immunity.Annu. Rev. Immunol.26, 677–704 (2008).

    Article CAS  Google Scholar 

  26. Lin, D.Y. et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors.Proc. Natl. Acad. Sci. USA105, 3011–3016 (2008).

    Article CAS  Google Scholar 

  27. Gordon, S. et al. Monocyte and macrophage heterogeneity.Nat. Rev. Immunol.5, 953–964 (2005).

    Article CAS  Google Scholar 

  28. Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8.Science303, 1526–1529 (2004).

    Article CAS  Google Scholar 

  29. Frankenberger, M., Sternsdorf, T., Pechumer, H., Pforte, A. & Ziegler-Heitbrock, H.W. Differential cytokine expression in human blood monocyte subpopulations: a polymerase chain reaction analysis.Blood87, 373–377 (1996).

    CAS PubMed  Google Scholar 

  30. de Waal Malefyt, R. et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression.J. Exp. Med.174, 915–924 (1991).

    Article CAS  Google Scholar 

  31. Younes, S.A. et al. HIV-1 viremia prevents the establishment of interleukin 2–producing HIV-specific memory CD4 T cells endowed with proliferative capacity.J. Exp. Med.198, 1909–1922 (2003).

    Article CAS  Google Scholar 

  32. Niemand, C. et al. Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3.J. Immunol.170, 3263–3272 (2003).

    Article CAS  Google Scholar 

  33. Trabattoni, D. et al. B7–H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression.Blood101, 2514–2520 (2003).

    Article CAS  Google Scholar 

  34. Zhong, Z. et al. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.Science264, 95–98 (1994).

    Article CAS  Google Scholar 

  35. Bright, J.J. et al. TGF-β inhibits IL-12–induced activation of Jak-STAT pathway in T lymphocytes.J. Immunol.161, 1772–1777 (1998).

    CAS PubMed  Google Scholar 

  36. Huber, M. et al. IRF4 is essential for IL-21–mediated induction, amplification and stabilization of the TH17 phenotype.Proc. Natl. Acad. Sci. USA105, 20846–20851 (2008).

    Article CAS  Google Scholar 

  37. El Kasmi, K.C. et al. General nature of the STAT3-activated anti-inflammatory response.J. Immunol.177, 7880–7888 (2006).

    Article CAS  Google Scholar 

  38. Williams, L. et al. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages.J. Immunol.172, 567–576 (2004).

    Article CAS  Google Scholar 

  39. Berlato, C. et al. Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation.J. Immunol.168, 6404–6411 (2002).

    Article CAS  Google Scholar 

  40. Urbani, S. et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion.J. Virol.80, 11398–11403 (2006).

    Article CAS  Google Scholar 

  41. Geng, L. et al. B7–H1 expression is upregulated in peripheral blood CD14+ monocytes of patients with chronic hepatitis B virus infection, which correlates with higher serum IL-10 levels.J. Viral Hepat.13, 725–733 (2006).

    Article CAS  Google Scholar 

  42. Shrestha, S. et al. Interleukin-10 gene (IL-10) polymorphisms and human papillomavirus clearance among immunosuppressed adolescents.Cancer Epidemiol. Biomarkers Prev.16, 1626–1632 (2007).

    Article CAS  Google Scholar 

  43. Swaminathan, S. Molecular biology of Epstein-Barr virus and Kaposi's sarcoma–associated herpesvirus.Semin. Hematol.40, 107–115 (2003).

    Article CAS  Google Scholar 

  44. Accapezzato, D. et al. Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection.J. Clin. Invest.113, 963–972 (2004).

    Article CAS  Google Scholar 

  45. Yao, S. et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection.Blood113, 5811–5818 (2009).

    Article CAS  Google Scholar 

  46. Boasso, A. et al. PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes.Clin. Immunol.129, 132–144 (2008).

    Article CAS  Google Scholar 

  47. Pandrea, I. et al. Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts.Blood109, 1069–1076 (2007).

    Article CAS  Google Scholar 

  48. Huang, X. et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis.Proc. Natl. Acad. Sci. USA106, 6303–6308 (2009).

    Article CAS  Google Scholar 

  49. Nelson, D.R. et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect.Hepatology38, 859–868 (2003).

    Article CAS  Google Scholar 

  50. Xiao, Y. et al. Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases.Virology372, 384–397 (2008).

    Article CAS  Google Scholar 

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Acknowledgements

We thank the subjects for their participation in this study. We also thank M. Legault and C. Grignon for their clinical assistance with the recruitment of study subjects. We are grateful to V.A. Evans and J.D. Schatzle for help in manuscript revision. E.A.S., L.T., M.E.-F. and J.V.G. are funded by the Canadian Institutes of Health Research (CIHR). N.H.S. holds a joint New Investigator Award from the Canadian Foundation for Infectious Diseases and CIHR. J.B. and J.-P.R. are clinician-scientists supported by Fonds de la recherche en santé du Québec. R.-P.S. is the Canada Research Chair in Human Immunology. This study was supported by funds from the US National Institutes of Health, the CIHR, the Canadian Foundation for AIDS Research, the Fonds de la recherche en santé du Québec AIDS and Infectious Disease Network (SIDA-MI) and the Canadian Network for Vaccines and Immunotherapeutics. This study was funded in part by the Intramural Program of the US National Institutes of Health. Vectors were generously provided by E. Cohen at the Institut de Recherches Cliniques de Montréal. The lentiviral vector pWPI (empty vector), packaging plasmid psPAX2 and envelope plasmid pMD2G were generously provided by D. Trono (University of Geneva).

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Author notes

  1. Franck P Dupuy and Lydie Trautmann: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Hôpital St.-Luc, Montréal, Québec, Canada

    Elias A Said, Franck P Dupuy, Lydie Trautmann, Yuwei Zhang, Yu Shi, Mohamed El-Far, Alessandra Noto, Petronela Ancuta, Yoav Peretz, Simone G Fonseca, Julien Van Grevenynghe, Julie Bruneau, Naglaa H Shoukry, Elias K Haddad & Rafick-Pierre Sekaly

  2. Département de Microbiologie et d'Immunologie, Laboratoire d'Immunologie, Université de Montréal, Québec, Canada

    Elias A Said, Franck P Dupuy, Lydie Trautmann, Yuwei Zhang, Yu Shi, Mohamed El-Far, Alessandra Noto, Petronela Ancuta, Yoav Peretz, Simone G Fonseca, Julien Van Grevenynghe, Elias K Haddad & Rafick-Pierre Sekaly

  3. Institute Nationale de la Santé et de la Recherche Médicale U743, CRCHUM, Université de Montréal, Montréal, Québec, Canada

    Elias A Said, Franck P Dupuy, Lydie Trautmann, Yuwei Zhang, Yu Shi, Mohamed El-Far, Alessandra Noto, Petronela Ancuta, Yoav Peretz, Simone G Fonseca, Julien Van Grevenynghe, Jean-Pierre Routy, Elias K Haddad & Rafick-Pierre Sekaly

  4. Vaccine & Gene Therapy Institute Florida, Port St. Lucie, Florida, USA

    Lydie Trautmann & Rafick-Pierre Sekaly

  5. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Brenna J Hill & Daniel C Douek

  6. Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre, McGill University, Montréal, Québec, Canada

    Mohamed R Boulassel & Jean-Pierre Routy

  7. Département de Médecine Familiale, Université de Montréal, Montréal, Québec, Canada.,

    Julie Bruneau

  8. Département de Médecine, Université de Montréal, Montréal, Québec, Canada.,

    Naglaa H Shoukry

  9. Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,

    Elias K Haddad & Rafick-Pierre Sekaly

Authors
  1. Elias A Said

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  2. Franck P Dupuy

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  3. Lydie Trautmann

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  4. Yuwei Zhang

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  5. Yu Shi

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  6. Mohamed El-Far

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  7. Brenna J Hill

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  8. Alessandra Noto

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  9. Petronela Ancuta

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  10. Yoav Peretz

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  11. Simone G Fonseca

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  12. Julien Van Grevenynghe

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  13. Mohamed R Boulassel

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  14. Julie Bruneau

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  15. Naglaa H Shoukry

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  16. Jean-Pierre Routy

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  17. Daniel C Douek

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  18. Elias K Haddad

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  19. Rafick-Pierre Sekaly

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Contributions

E.A.S. conducted all experiments and wrote the manuscript. F.P.D. participated in performing and planning the experiments inFigure 1b,c andSupplementary Figures 2 and6a,c–e. L.T. participated in performing and planning the experiments inFigures 1,3a,d,4a,c and5a. Y.Z. prepared the vectors used for the transduction of Cos cells and participated in the experiments inFigures 3i,5b,6e andSupplementary Figure 3a. Y.S. participated in the experiments inFigures 6a–c andSupplementary Figure 5d. M.E.-F. participated in the experiments inFigure 5c andSupplementary Figure 5. B.J.H. measured 16S DNA and soluble CD14 levels. A.N. participated in the experiments inFigure 5c. P.A. participated in the experiments inFigure 3. Y.P. participated in the experiments inFigure 6e andSupplementary Figure 6b,c,e. S.G.F. participated in the experiments inFigure 6e andSupplementary Figure 6b,c. J.V.G. participated in the experiments inFigure 1a,b. M.R.B., J.B., N.H.S. and J.-P.R. provided donor samples and data about the viral load and cell counts. D.C.D. performed 16S and soluble CD14 measurement and participated in the manuscript writing. E.K.H. participated in experimental design and in the manuscript writing. R.-P.S. supervised the project.

Corresponding author

Correspondence toRafick-Pierre Sekaly.

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Said, E., Dupuy, F., Trautmann, L.et al. Programmed death-1–induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection.Nat Med16, 452–459 (2010). https://doi.org/10.1038/nm.2106

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