Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens

Toll-like receptors (TLRs) are ancient microbial pattern recognition recept ors highly conserved from Drosophila to humans. To investigate if subsets o f human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c(+) immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studie d their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasma cytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR ex pression profiles, monocytes respond to the known microbial ligands for TLR 2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), b y producing tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6. In c ontrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, Cp G-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), b y producing IFN-alpha. CD11c(+) imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-alpha a nd to viral double-stranded RNA-like molecule poly I:C, by producing IFN-al pha and IL-12. The expression of distinct sets of TLRs and the correspondin g difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evo lutionary pathways to recognize different microbial antigens.