title: Activation of NF-κB in CD8+ dendritic cells Ex Vivo by the γ134.5 null mutant correlates with immunity against herpes simplex virus 1.
abstract: The γ(1)34.5 protein of herpes simplex viruses (HSV) is essential for virulence. Accordingly, an HSV mutant lacking γ(1)34.5 is attenuated in vivo. Despite its vaccine potential, the mechanism by which the γ(1)34.5 null mutant triggers protective immunity is unknown. In this report we show that vaccination with the γ(1)34.5 null mutant protects against lethal challenge from wild-type virus via IκB kinase in dendritic cells (DCs), which sense virus-associated molecular patterns. Unlike mock-treated DCs, DCs primed with the γ(1)34.5 null mutant ex vivo mediate resistance to wild-type HSV after adoptive transfer into naïve mice. Furthermore, the γ(1)34.5 null mutant activates IκB kinase, which facilitates p65/RelA phosphorylation and nuclear translocation, resulting in DC maturation. While unable to produce infectious virus in DCs, this mutant virus expresses early and late genes. In its abortive infection, the γ(1)34.5 null mutant induces protective immunity more effectively in CD8(+) DCs than in CD8(-) DCs. This is mirrored by a higher level of interleukin-6 (IL-6) and IL-12 secretion by CD8(+) DCs than CD8(-) DCs. Remarkably, inhibition of p65/RelA phosphorylation or nuclear translocation in CD8(+) DCs disrupts protective immunity. These results suggest that engagement of the γ(1)34.5 null mutant with CD8(+) DCs elicits innate immunity to activate NF-κB, which translates into protective immunity.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Huali
authors.initials: H
authors.lastname: Jin
authors.forename: Yijie
authors.initials: Y
authors.lastname: Ma
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yan
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.forename: Bin
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007109:Immunity; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D017384:Sequence Deletion; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D016827:CD8 Antigens; D016328:NF-kappa B; D014764:Viral Proteins
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