title: Inhibitory effects of cytomegalovirus proteins US2 and US11 point to contributions from direct priming and cross-priming in induction of vaccinia virus-specific CD8(+) T cells.
abstract: The extent to which naive CD8(+) CTLs (T(CD8)(+)) are primed by APCs presenting endogenous Ags (direct priming) or Ags acquired from other infected cells (cross-priming) is a critical topic in basic and applied immunology. To examine the contribution of direct priming in the induction of VV-specific T(CD8)(+), we generated recombinant vaccinia viruses that express human CMV proteins (US2 and US11) that induce the destruction of newly synthesized MHC class I molecules. Expression of US2 or US11 was associated with a 24-63% decrease in numbers of primary or secondary VV-specific T(CD8)(+) responding to i.p. infection. Using HPLC-isolated peptides from VV-infected cells, we show that US2 and US11 selectively inhibit T(CD8)(+) responses to a subset of immunogenic VV determinants. Moreover, VV-US2 and lysates from VV-infected histoincompatible cells elicit T(CD8)(+) specific for a similar subset of VV determinants. These findings indicate that US2 and US11 can function in vivo to interfere with the activation of virus-specific T(CD8)(+). Furthermore, they suggest that 1) both cross-priming and direct priming contribute significantly to the generation of VV-specific T(CD8)(+), 2) the sets of immunogenic vaccinia virus determinants generated by cross-priming and direct priming are not completely overlapping, and 3) cross-priming overrides the effects of cis-acting viral interference with the class I Ag presentation pathway.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Sameh
authors.initials: S
authors.lastname: Basta
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006183:H-2 Antigens / Q000032:analysis / Q000502:physiology; D064532:Histocompatibility Antigen H-2D; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016601:RNA-Binding Proteins / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014616:Vaccinia virus / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D007371:Interferon-gamma