High-avidity antitumor T-cell generation by toll receptor 8-primed, myeloid- derived dendritic cells is mediated by IL-12 production.
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.
Xu
Shuwen
S
Harrison Department of Surgical Research, University of Pennsylvania, Philadelphia, PA, USA.
Koldovsky
Ursula
U
Xu
Min
M
Wang
Daniel
D
Fitzpatrick
Elizabeth
E
Son
Gilsoo
G
Koski
Gary
G
Czerniecki
Brian J
BJ
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*
D015703:Antigens, CD; D007093:Imidazoles; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D007371:Interferon-gamma; C402365:resiquimod