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

Nature Medicine volume 21, pages 327–334 (2015)Cite this article

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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.

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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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  1. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Jonathan H Chen, Curtis J Perry, Yao-Chen Tsui, Matthew M Staron, Ian A Parish, Claudia X Dominguez & Susan M Kaech

  2. Center for Molecular Medicine, The University of Connecticut Health Center, Farmington, Connecticut, USA

    Daniel W Rosenberg

  3. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Susan M Kaech

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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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