An in vitro screen employing human neonatal dendritic cells identifies distinct synergy between Toll-like receptor and C-type lectin receptor agonists (VAC10P.966)

Abstract

Due to impairments in cell-mediated immunity, newborns are markedly susceptible to infection with intracellular pathogens. Impaired newborn immunity includes a reduced response to Toll-like Receptor agonists (TLRAs) by dendritic cells (DCs), placing them at risk for infection and limiting Th1-responses to many vaccines. Our hypothesis was that dual stimulation with TLRAs and C-type Lectin Receptor agonists (CLRAs) may overcome the reduced response of newborn DCs to common vaccine formulations. We screened TLRAs, CLRAs and their combinations for their ability to induce Th1-polarizing cytokine production from neonatal dendritic cells. Human adult- and cord blood monocyte-derived DCs (MoDCs) were generated in the presence of autologous plasma and stimulated for 18 hours. Cytokines and markers for cellular toxicity were measured to assess correlates of immunogenicity and reactogenicity. Dual activation of newborn DCs with a TLR8 agonist (R848) and a Mincle agonist (TDB) or with a TLR4 agonist (MPLA or GLA) and a Dectin-1 agonist (alkali-treated Zymosan) synergistically enhanced the production of the T-cell activating and -polarizing cytokines TNF-α, IL-12p70 and IL-1β. Our data suggest that targeting vaccinal antigens to the endocytic receptors Mincle or Dectin-1 is a powerful approach to induce Th1-mediated immunity in newborns. This study has the potential to inform development of novel adjuvanted neonatal vaccines and reduce infections in infants.