Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells.
Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNF-alpha responses to most known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-alpha responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imidazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Th1-polarizing cytokines TNF-alpha and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2, -4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myeloid dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation of IkappaB-alpha in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.
Levy
Ofer
O
Division of Infectious Diseases, Children's Hospital Boston, Boston, MA 02115, USA. ofer.levy@childrens.harvard.edu
Suter
Eugénie E
EE
Miller
Richard L
RL
Wessels
Michael R
MR
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000276:immunology / Q000378:metabolism; D007231:Infant, Newborn; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D048051:p38 Mitogen-Activated Protein Kinases