title: CD8+ T cell responses following replication-defective adenovirus serotype 5 immunization are dependent on CD11c+ dendritic cells but show redundancy in their requirement of TLR and nucleotide-binding oligomerization domain-like receptor signaling.
abstract: Replication-defective adenovirus serotype 5 (rAd5) is the most potent recombinant vector for eliciting CD8 T cell responses in humans. In this study, the innate mechanisms that influence T cell responses following rAd5 immunization were assessed in mice. Using rAd5 expressing enhanced GFP (eGFP-rAd5), we show that rAd5 transfects CD11c(+) dendritic cells (DCs) in draining lymph nodes in vivo following s.c. or i.m. immunization. Among distinct DC subsets, eGFP expression was highest in CD11c(+)CD8(-)B220(-) with a lower frequency detected in CD11c(+)CD8(+)B220(-) and CD11c(+)B220(+) plasmacytoid DCs. CD11c(+) DCs but not CD11c(-) cells from mice immunized with rAd5 encoding the SIINFEKL peptide induced proliferation of naive OT-I CD8 T cells. Furthermore, CD11c(+)CD8(+)B220(-) was the most potent DC subset for eliciting naive OT-I CD8 T cell proliferation. Of note, mice with pre-existing immunity to rAd5 had a substantial decrease in eGFP expression in DCs, which was associated with approximately 2-fold decrease in Th1 and complete inhibition of CD8 responses. Thus, pre-existing rAd5 immunity has a greater influence on CD8 compared with CD4 T cell responses. In terms of how innate cytokines and signaling pathways influenced T cell immunity following rAd5 immunization, we show that the magnitude and quality of CD8 T cell responses are partially dependent on MyD88 but independent of IL-12, type I IFN, apoptosis-associated speck-like protein, nucleotide-binding oligomerization domain-like receptor protein 3, and IL-1. Taken together, these data demonstrate a critical role for CD11c(+) DCs for CD8 responses but striking redundancy for innate cytokines and signaling by TLR and nucleotide-binding oligomerization domain-like receptor pathways.
authors.affiliation: Cellular Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ross W B
authors.initials: RW
authors.lastname: Lindsay
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Quinn
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wille-Reece
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mattei
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.forename: Sudhir P
authors.initials: SP
authors.lastname: Kasturi
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.forename: Jason G D
authors.initials: JG
authors.lastname: Gall
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Spies
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D039521:CD11c Antigen / Q000096:biosynthesis* / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003673:Defective Viruses / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D007113:Immunity, Innate; D016130:Immunophenotyping; D007370:Interferon Type I / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000502:physiology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014771:Virion / Q000276:immunology / Q000472:pathogenicity
chemical_list: D039521:CD11c Antigen; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; C549161:NLRC5 protein, mouse; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D014765:Viral Vaccines; D018664:Interleukin-12