title: Blocking Virus Replication during Acute Murine Cytomegalovirus Infection Paradoxically Prolongs Antigen Presentation and Increases the CD8+ T Cell Response by Preventing Type I IFN-Dependent Depletion of Dendritic Cells.
abstract: Increasing amounts of pathogen replication usually lead to a proportionate increase in size and effector differentiation of the CD8+T cell response, which is attributed to increased Ag and inflammation. Using a murine CMV that is highly sensitive to the antiviral drug famciclovir to modulate virus replication, we found that increased virus replication drove increased effector CD8+T cell differentiation, as expected. Paradoxically, however, increased virus replication dramatically decreased the size of the CD8+T cell response to two immunodominant epitopes. The decreased response was due to type I IFN-dependent depletion of conventional dendritic cells and could be reproduced by specific depletion of dendritic cells from day 2 postinfection or by sterile induction of type I IFN. Increased virus replication and type I IFN specifically inhibited the response to two immunodominant epitopes that are known to be dependent on Ag cross-presented by DCs, but they did not inhibit the response to "inflationary" epitopes whose responses can be sustained by infected nonhematopoietic cells. Our results show that type I IFN can suppress CD8+T cell responses to cross-presented Ag by depleting cross-presenting conventional dendritic cells.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; and.
authors.forename: Christopher P
authors.identifier: 0000-0002-5302-8774
authors.initials: CP
authors.lastname: Loo
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Christopher M
authors.identifier: 0000-0003-1370-7198
authors.initials: CM
authors.lastname: Snyder
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; and hillan@ohsu.edu.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Hill
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006566:Herpesviridae Infections / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology; D051379:Mice; D018146:Muromegalovirus / Q000276:immunology; D014779:Virus Replication
chemical_list: D007370:Interferon Type I