Differential requirement for the IKKβ/NF-kB signaling module in regulating TLR-versus RLR-induced type 1 IFN expression in dendritic cells

Host innate-immune responses are tailored by cell type to control and eradicate specific infectious agents. For example, an acute RNAvirus infection can result in high-level expression of type 1 IFNs by both conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs), but whereas cDCs preferentially use RIG-I-like receptor (RLR) signaling to produce type 1 IFNs, pDCs predominantly use TLRs to induce these cytokines. We previously found that the IkB kinase β (IKKβ)/NF-kB pathway regulates early IFN-β expression, but not the magnitude of type 1 IFN expression following RLR engagement. In this study, we use IKKβ inhibition and mice deficient in IKKβ or canonical NF-kB subunits (p50, RelA/p65, and cRel) to demonstrate that the IKKβ/NFkB axis is critical for virus-induced type 1 IFN expression in pDCs, but not in cDCs. We also reveal a crucial and more general requirement for IKKβ/NF-kB in TLR-but not RLR-induced expression of type 1 IFNs and inflammatory cytokines. Together, these findings reveal a previously unappreciated specificity of the IKKb/NF-kB signaling axis in regulation of antimicrobial responses by different classes of pattern recognition receptors, and therefore by individual cell types reliant on particular pattern recognition receptors for their innate-immune transcriptional responses.