Combined Toll-like receptor agonists synergistically increase production of inflammatory cytokines in human neonatal dendritic cells.

Dendritic cells (DC) are thought to be responsible for the reduced ability of human newborns to induce protective T-helper 1 (Th1) immune responses. The key player in Th1 differentiation, interleukin-12 (IL-12), is primarily produced in response to Toll-like receptor (TLR) binding by adult DC but not by neonatal DC. The potential use of various TLR agonist combinations for initiating neonatal monocyte-derived DC to prime Th1 responses was investigated. Single TLR ligands induced maturation only in adult DC; neonatal DC matured with combined targeting of TLR3/TLR8 or TLR4/TLR8, based on the expression of maturation markers. Similarly, the synergistic effects of combined TLR ligands could also be shown with adult and neonatal cytokine production, but different expression patterns were noted. In particular, IL-12p70 was produced by neonatal DC exclusively after combined TLR stimulation. Surprisingly, it was found that supernatants of combined stimulated neonatal DC could induce interferon-gamma production in autologous naïve T cells. Moreover, this interferon-gamma secretion was blocked by anti-IL-12p70 antibodies and increased after addition of recombined IL-12. In conclusion, these findings underline the differences between adult and neonatal DC and might suggest new strategies for promoting newborn Th1 immunity in response to pathogens and vaccine antigens.