Background
Newborns suffer frequent infection and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant, but may confer a Th2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes (Mos) demonstrate impaired Th1-polarizing responses to many TLR agonists due to plasma adenosine acting via cAMP. TLR8 agonists, including imidazoquinolines (IMQs) such as the small synthetic 3M-002, induce adult-level TNF from neonatal Mos, but the scope and mechanisms of IMQ-induced activation of neonatal Mos and Mo-derived dendritic cells (MoDCs) have not been reported.
Objectives
To characterize IMQ-induced activation of neonatal Mos and MoDCs.
Methods
Neonatal cord and adult peripheral blood Mos and MoDCs were cultured in autologous plasma; Alum- and TLR agonist-induced cytokines and co-stimulatory molecules were measured. TLR8 and inflammasome function were assayed using siRNA and western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist–induced cytokine responses was defined in Rhesus macaque whole blood ex vivo.
Results
IMQs were more potent and effective than Alum at inducing TNF and IL-1β from Mos. 3M-002 induced robust TLR pathway transcriptome activation and Th1-polarizing cytokine production in neonatal and adult Mos and MoDCs, signaling via TLR8 in an adenosine/cAMP- refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1β production, but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8-IMQs induced robust TNF and IL-1β in whole blood of Rhesus macaques at birth and infancy.
Conclusions
IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust Mo and MoDC activation and represent promising neonatal adjuvants.
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