The authors initially set out to examine how YF-17D initiates an adaptive immune response. They showed that YF-17D activates several subsets of human and mouse DCs in vitro. In response to YF-17D, monocyte-derived DCs showed increased expression of the p40 subunit of interleukin-12 (IL-12), as well as the pro-inflammatory cytokines IL-6, tumour-necrosis factor, CC-chemokine ligand 2 (CCL2) and CXC-chemokine ligand 10 (CXCL10), and the co-stimulatory molecules CD80 and CD86. Plasmacytoid DCs also produced large amounts of interferon-α (IFNα), which activates an antiviral programme in certain cells, in response to YF-17D.
Because DCs recognize microorganisms through pattern-recognition receptors — such as the TLR family (each member of which binds distinct microbial components) — the authors then assessed how YF-17D activates DCs by examining DCs from mice that are deficient in various TLRs and TLR adaptor molecules. The absence of the adaptor molecules MyD88 (myeloid differentiation primary-response gene 88; which associates with all TLRs except TLR3) or TIRAP (Toll/IL-1-receptordomain-containing adaptor protein; which only associates with TLR2 and TLR4) resulted in reduced IL-6 and IL-12p40 expression, indicating that at least two adaptor molecules are involved in YF-17D-induced DC activation. The absence of TLR2, TLR7 or TLR9 (but not TLR4) also impaired IL-6 and IL-12p40 expression in response to YF-17D, and YF-17D activated cells transfected with TLR8, indicating that YF-17D can induce signalling through distinct TLRs.
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