title: High-avidity antitumor T-cell generation by toll receptor 8-primed, myeloid- derived dendritic cells is mediated by IL-12 production.
abstract: BACKGROUND
  High-level production of heterodimeric p70 interleukin (IL)-12 by myeloid-derived dendritic cells (DCs) requires 2 signals: interferon gamma (IFN-gamma) and a maturation signal provided by CD40 ligation (CD40L) or lipopolysaccharide (LPS).
  
  
  METHODS
  In the current study we demonstrate that signaling through toll-like receptor (TLR) 8, but not TLR3, TLR2, or TLR4, provides a priming signal to myeloid-derived DC for high IL-12 p70 heterodimer production.
  
  
  RESULTS
  All the TLR agonists induced maturation of DC as evidenced by increased expression of CD83, CD80, and CD86. Both IFN-gamma and TLR7/8 agonist R848 increased expression of TLR8 in immature monocyte-derived DCs. The combination of TLR7/8 agonist R848 and maturation signals LPS or CD40L induced high-level expression of IL-12p35 and p40 similar to that induced by IFN-gamma plus LPS. In contrast, receptor agonists specific for TLR7 did not prime for IL-12 production. The p70 IL-12 produced by the TLR8-primed DC polarized CD4+ T for Th1 cytokine production and induced CD8+ T cells, displaying high functional avidity with enhanced tumor cell recognition.
  
  
  CONCLUSIONS
  The data suggest that toll 8 receptor agonists are useful for inducing type-1 polarized DCs for vaccine design in treating cancer and infectious disease.
authors.affiliation: Harrison Department of Surgical Research, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.forename: Ursula
authors.initials: U
authors.lastname: Koldovsky
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Daniel
authors.initials: D
authors.lastname: Wang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fitzpatrick
authors.forename: Gilsoo
authors.initials: G
authors.lastname: Son
authors.forename: Gary
authors.initials: G
authors.lastname: Koski
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism*; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D007093:Imidazoles; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D007371:Interferon-gamma; C402365:resiquimod