Imidazoquinoline Toll-like Receptor 8 Agonists Activate Human Newborn Monocytes and Dendritic Cells Through Adenosine-Refractory and caspase-1-dependent Pathways

J Allergy Clin Immunol. 2012 Jul;130(1):195-204.e9. doi: 10.1016/j.jaci.2012.02.042. Epub 2012 Apr 21.

Abstract

Background: Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T(H)2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T(H)1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported.

Objective: We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs.

Methods: Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA 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 monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T(H)1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-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 monocyte and MoDC activation and represent promising neonatal adjuvants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism*
  • Adjuvants, Immunologic
  • Adult
  • Alum Compounds
  • Animals
  • Caspase 1 / metabolism*
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Humans
  • Imidazoles / pharmacology*
  • Infant, Newborn
  • Macaca mulatta
  • Monocytes / immunology*
  • Quinolines / pharmacology*
  • Toll-Like Receptor 8 / agonists*

Substances

  • 3M 002
  • Adjuvants, Immunologic
  • Alum Compounds
  • Cytokines
  • Imidazoles
  • Quinolines
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • aluminum sulfate
  • quinoline
  • Caspase 1
  • Adenosine