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Dendritic Cell Programming by Cytomegalovirus Stunts Naive T Cell Responses via the PD-L1/PD-1 Pathway¹

Chris A. Benedict^2,*, Andrea Loewendorf^*, Zacarias Garcia, Bruce R. Blazar and Edith M. Janssen^2,

^* Department of Molecular Immunology and Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455

Early during infection, CMV targets dendritic cells (DC) and alters their functions. Herein we show that CMV-infected DC maintain the ability to present both virus-derived and exogenous Ags, but that they actively induce tolerance or anergy in Ag-specific T cells. CMV accomplishes this by selectively maintaining high-level expression of the negative costimulatory molecule programmed death ligand-1 (PD-L1), while commensurately down-regulating positive costimulatory molecules and MHC on the DC surface. Consequently, CD4 and CD8 T cells activated by these infected DC have a stunted phenotype, characterized by poor proliferation, effector function. and recall responses. Blocking PD-L1, but not PD-L2, during direct priming of naive T cells by infected DC significantly restores Ag-specific T cell functions. Using systems where direct and cross-priming of T cells can be distinguished revealed that PD-L1/PD-1 signaling contributes only when naive T cells are primed directly by infected DC, and not upon cross-presentation of viral Ags by uninfected DC. These data suggest that murine CMV programs infected DC during acute infection to inhibit early host adaptive antiviral responses by tipping the balance between negative and positive cosignals.

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 in part by National Institutes of Health Grants R01 AI 34495, CA72669, and P01 AI056299 (to B.R.B.), American Heart Association Grant 0330064N (to C.A.B.), and Leukemia and Lymphoma Society 3248-05 (to E.M.J.).

² Address correspondence and reprint requests to Dr. Edith M. Janssen and Dr. Chris A. Benedict, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail addresses: edith.janssen{at}cchmc.org and benedict{at}liai.org

³ Abbreviations used in this paper: DC, dendritic cell; HCMV, human CMV; mDC, dendritic cells derived from bone marrow; MCMV, murine CMV; PD-L, programmed death ligand; PI, propidium iodide; 7-AAD, 7-aminoactinomycin D.