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PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8⁺ T Lymphocytes in the Liver¹

Holly Maier^*, Masanori Isogawa^*, Gordon J. Freeman^, and Francis V. Chisari^2,*

^* Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and Department of Medicine, Harvard Medical School, Boston, MA 02115

Mechanisms contributing to the development of chronic viral infections, including chronic hepatitis B virus (HBV) infections, are not well understood. We have shown recently that production of IFN-, an important antiviral cytokine, by HBV-specific CTLs is rapidly induced when they enter the liver of HBV transgenic mice, and then rapidly suppressed, despite the continued presence of Ag. Suppression of IFN- production by the CTLs coincides with the up-regulation of programmed cell death (PD)-1, a cell surface signaling molecule known to inhibit T cell function. To determine whether PD-1 plays a role in the functional suppression of IFN- secretion by CTLs, we treated HBV transgenic mice with blocking Abs specific for PD ligand (PD-L)1, the most widely expressed PD-1 ligand, and adoptively transferred HBV-specific CTLs. Treatment with anti-PD-L1 Abs resulted in a delay in the suppression of IFN--producing CTLs and a concomitant increase in the absolute number of IFN--producing CTLs in the liver. These results indicate that PD-1:PD-L1 interactions contribute to the suppression of IFN- secretion observed following Ag recognition in the liver. Blockade of inhibitory pathways such as PD-1:PD-L1 may reverse viral persistence and chronic infection in cases in which the CTL response is suppressed by this mechanism.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 CA40489-21 (to F.V.C.) and P01 AI56299 and a Gates Grand Challenges in Global Health award (to G.J.F.). H.M. was supported by National Institutes of Health Grant T32 AI07244-22 and a Cancer Research Institute postdoctoral fellowship.

² Address correspondence and reprint requests to Dr. Francis V. Chisari, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, SBR10, La Jolla, CA 92037. E-mail address: fchisari{at}scripps.edu

³ Abbreviations used in this paper: HBV, hepatitis B virus; IHL, intrahepatic lymphocyte; Irr mAb, irrelevant mAb; LCMV, lymphocytic choriomeningitis virus; LNPC, liver nonparenchymal cell; LSEC, liver sinusoidal endothelial cell; PD, programmed cell death; PD-L, PD ligand; sALT, serum alanine aminotransferase.

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