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Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection

Abstract

More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE2) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE2 inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections.

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Figure 1: PGE2 signaling directly suppresses CTL function via the receptors EP2 and EP4 during LCMV infection.
Figure 2: PGE2-deficient mice have greater numbers of antigen-specific cytokine-producing CD8+ T cells.
Figure 3: PD-1 expression in antiviral CD8+ T cells in WT, EP2/4–double knockout and mPGES1-knockout mice.
Figure 4: Combination blockade of PD-L1 and PGE2 signaling substantially augments antiviral CTL numbers and function, restores immunodominance hierarchy, and enhances viral control.
Figure 5: Pharmacologic COX-2 inhibition with celecoxib enhances the effects of PD-L1 blockade.
Figure 6: PGE2 signaling suppresses virus-specific CD8+ T cell survival but not division.

References

  1. Shin, H. & Wherry, E.J. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408–415 (2007).

    CAS  PubMed  Google Scholar 

  2. Virgin, H.W., Wherry, E.J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).

    CAS  PubMed  Google Scholar 

  3. Wherry, E.J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    CAS  PubMed  Google Scholar 

  4. Wherry, E.J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    CAS  PubMed  Google Scholar 

  5. Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Staron, M.M. et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity 41, 802–814 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Barber, D. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    CAS  Google Scholar 

  8. Mueller, S. et al. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl. Acad. Sci. USA 104, 15430–15435 (2007).

    CAS  PubMed  Google Scholar 

  9. Baitsch, L. et al. Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Jin, H.T., Ahmed, R. & Okazaki, T. Role of PD-1 in regulating T-cell immunity. Curr. Top. Microbiol. Immunol. 350, 17–37 (2011).

    CAS  PubMed  Google Scholar 

  11. Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Topalian, S.L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    CAS  PubMed  Google Scholar 

  14. Tinoco, R., Alcalde, V., Yang, Y., Sauer, K. & Zuniga, E.I. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31, 145–157 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Redford, P.S., Murray, P.J. & O'Garra, A. The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol. 4, 261–270 (2011).

    CAS  Google Scholar 

  18. Hara, S. et al. Prostaglandin E synthases: understanding their pathophysiological roles through mouse genetic models. Biochimie 92, 651–659 (2010).

    CAS  PubMed  Google Scholar 

  19. Harris, S.G., Padilla, J., Koumas, L., Ray, D. & Phipps, R.P. Prostaglandins as modulators of immunity. Trends Immunol. 23, 144–150 (2002).

    CAS  PubMed  Google Scholar 

  20. Kalinski, P. Regulation of immune responses by prostaglandin e2. J. Immunol. 188, 21–28 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Linnemeyer, P.A. & Pollack, S.B. Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells. J. Immunol. 150, 3747–3754 (1993).

    CAS  PubMed  Google Scholar 

  22. Sreeramkumar, V., Fresno, M. & Cuesta, N. Prostaglandin E2 and T cells: friends or foes? Immunol. Cell Biol. 90, 579–586 (2012).

    CAS  PubMed  Google Scholar 

  23. Strassmann, G., Patil-Koota, V., Finkelman, F., Fong, M. & Kambayashi, T. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J. Exp. Med. 180, 2365–2370 (1994).

    CAS  PubMed  Google Scholar 

  24. Demeure, C.E., Yang, L.P., Desjardins, C., Raynauld, P. & Delespesse, G. Prostaglandin E2 primes naive T cells for the production of anti-inflammatory cytokines. Eur. J. Immunol. 27, 3526–3531 (1997).

    CAS  PubMed  Google Scholar 

  25. Gabrilovich, D.I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rahmouni, S. et al. Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice. Biochem. J. 384, 469–476 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Paley, M.A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Blackburn, S.D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    CAS  PubMed  Google Scholar 

  29. Blackburn, S.D., Shin, H., Freeman, G.J. & Wherry, E.J. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc. Natl. Acad. Sci. USA 105, 15016–15021 (2008).

    CAS  PubMed  Google Scholar 

  30. Khan, M.M., Tran, A.C. & Keaney, K.M. Forskolin and prostaglandin E2 regulate the generation of human cytolytic T lymphocytes. Immunopharmacology 19, 151–161 (1990).

    CAS  PubMed  Google Scholar 

  31. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R.P. & Kalinski, P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118, 5498–5505 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Pettersen, F.O. et al. An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J. Virol. 85, 6557–6566 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Su, Y., Jackson, E.K. & Gorelik, E. Receptor desensitization and blockade of the suppressive effects of prostaglandin E(2) and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes. Cancer Immunol. Immunother. 60, 111–122 (2011).

    CAS  PubMed  Google Scholar 

  34. Brudvik, K.W. & Taskén, K. Modulation of T cell immune functions by the prostaglandin E(2)–cAMP pathway in chronic inflammatory states. Br. J. Pharmacol. 166, 411–419 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Vang, T. et al. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J. Exp. Med. 193, 497–507 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Chemnitz, J.M., Parry, R.V., Nichols, K.E., June, C.H. & Riley, J.L. 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 (2004).

    CAS  PubMed  Google Scholar 

  37. Jin, H.-T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 107, 14733–14738 (2010).

    CAS  PubMed  Google Scholar 

  38. Zajac, A.J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).

    CAS  PubMed  Google Scholar 

  41. Callus, B.A. & Vaux, D.L. Caspase inhibitors: viral, cellular and chemical. Cell Death Differ. 14, 73–78 (2007).

    CAS  PubMed  Google Scholar 

  42. Aandahl, E.M. et al. Additive effects of IL-2 and protein kinase A type I antagonist on function of T cells from HIV-infected patients on HAART. AIDS 13, F109–F114 (1999).

    CAS  PubMed  Google Scholar 

  43. Aandahl, E.M. et al. Protein kinase A type I antagonist restores immune responses of T cells from HIV-infected patients. FASEB J. 12, 855–862 (1998).

    CAS  PubMed  Google Scholar 

  44. Kvale, D. et al. Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment. AIDS 20, 813–820 (2006).

    CAS  PubMed  Google Scholar 

  45. Johansson, C.C. et al. Treatment with type-2 selective and non-selective cyclooxygenase inhibitors improves T-cell proliferation in HIV-infected patients on highly active antiretroviral therapy. AIDS 18, 951–952 (2004).

    CAS  PubMed  Google Scholar 

  46. Algra, A.M. & Rothwell, P.M. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 13, 518–527 (2012).

    CAS  PubMed  Google Scholar 

  47. Baron, J.A. et al. A randomized trial of aspirin to prevent colorectal adenomas. N. Engl. J. Med. 348, 891–899 (2003).

    CAS  PubMed  Google Scholar 

  48. Grayson, J.M., Weant, A.E., Holbrook, B.C. & Hildeman, D. Role of Bim in regulating CD8+ T-cell responses during chronic viral infection. J. Virol. 80, 8627–8638 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lopes, A.R. et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J. Clin. Invest. 118, 1835–1845 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, L. & Insel, P.A. The pro-apoptotic protein Bim is a convergence point for cAMP/protein kinase A- and glucocorticoid-promoted apoptosis of lymphoid cells. J. Biol. Chem. 279, 20858–20865 (2004).

    CAS  PubMed  Google Scholar 

  51. Zhang, L. et al. Gene expression signatures of cAMP/protein kinase A (PKA)-promoted, mitochondrial-dependent apoptosis. Comparative analysis of wild-type and cAMP-deathless S49 lymphoma cells. J. Biol. Chem. 283, 4304–4313 (2008).

    CAS  PubMed  Google Scholar 

  52. Moujalled, D. et al. Cyclic-AMP-dependent protein kinase A regulates apoptosis by stabilizing the BH3-only protein Bim. EMBO Rep. 12, 77–83 (2011).

    CAS  PubMed  Google Scholar 

  53. Zambon, A.C., Wilderman, A., Ho, A. & Insel, P.A. Increased expression of the pro-apoptotic protein BIM, a mechanism for cAMP/protein kinase A (PKA)-induced apoptosis of immature T cells. J. Biol. Chem. 286, 33260–33267 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. West, E.E. et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Invest. 123, 2604–2615 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bachmann, M.F., Wolint, P., Walton, S., Schwarz, K. & Oxenius, A. Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur. J. Immunol. 37, 1502–1512 (2007).

    CAS  PubMed  Google Scholar 

  56. Blattman, J.N. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9, 540–547 (2003).

    CAS  PubMed  Google Scholar 

  57. Kennedy, C.R. et al. Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat. Med. 5, 217–220 (1999).

    CAS  PubMed  Google Scholar 

  58. Schneider, A. et al. Generation of a conditional allele of the mouse prostaglandin EP4 receptor. Genesis 40, 7–14 (2004).

    CAS  PubMed  Google Scholar 

  59. Trebino, C.E. et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Natl. Acad. Sci. USA 100, 9044–9049 (2003).

    CAS  PubMed  Google Scholar 

  60. Jacob, J. & Baltimore, D. Modelling T-cell memory by genetic marking of memory T cells in vivo. Nature 399, 593–597 (1999).

    CAS  PubMed  Google Scholar 

  61. Joshi, N.S. et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ahmed, R., Salmi, A., Butler, L.D., Chiller, J.M. & Oldstone, M.B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160, 521–540 (1984).

    CAS  PubMed  Google Scholar 

  63. Fuller, M.J., Khanolkar, A., Tebo, A.E. & Zajac, A.J. Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J. Immunol. 172, 4204–4214 (2004).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge C. Hao (Vanderbilt University, Nashville, Tennessee, USA) and E. Wherry (University of Pennsylvania, Philadelphia, Pennsylvania, USA) for generously providing EP2- and EP4-deficient mice and KbGP34 tetramers, respectively. This work was supported by RO1AI074699 (S.M.K.), the Yale Medical Scientist Training Program (T32GM07205 to J.H.C.) and the Howard Hughes Medical Institute (S.M.K.).

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J.H.C. designed and performed experiments, analyzed data, and wrote the paper; C.J.P., Y.-C.T., M.M.S. and C.X.D. designed and performed experiments; I.A.P. analyzed data and designed experiments; D.W.R. provided critical reagents; S.M.K. designed experiments, analyzed data and wrote the paper.

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Correspondence to Susan M Kaech.

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J.H.C. and S.M.K. have applied for a patent based in part on the findings outlined in this paper.

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Chen, J., Perry, C., Tsui, YC. et al. Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat Med 21, 327–334 (2015). https://doi.org/10.1038/nm.3831

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