Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates

Blood. 2012 Mar 1;119(9):2044-55. doi: 10.1182/blood-2011-10-388579. Epub 2012 Jan 12.


TLR ligands (TLR-Ls) represent novel vaccine adjuvants, but their immunologic effects in humans remain poorly defined in vivo. In the present study, we analyzed the innate responses stimulated by different TLR-Ls in rhesus macaques. MPL (TLR4-L), R-848 (TLR7/8-L), or cytosine-phosphate-guanine oligodeoxynucleotide (TLR9-L) induced a rapid and robust expansion of blood neutrophils, with a concomitant reduction in PBMCs. Furthermore, all TLR-Ls induced rapid (3-8 hours) expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L mobilized the CD14(+)CD16(+) and CD14(dim)CD16(++) monocytes, and only TLR7/8-L and TLR9-L induced activation of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs), production of IP-10 and type-I IFN, and expression of type-I IFN-related and chemokine genes in the blood. In the draining lymph nodes (LNs), consistent with the effects in blood, all TLR-Ls induced expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L expanded the activated CD14(+)CD16(+) cells. TLR4-L and TLR9-L differentially induced the expansion of mDCs and pDCs (1-3 days), but did not activate DCs. In contrast, TLR7/8-L did not induce DC expansion, but did activate mDCs. Finally, both TLR9-L and TLR7/8-L induced the expression of genes related to chemokines and type-I IFNs in LNs. Thus different TLR-Ls mediate distinct signatures of early innate responses both locally and systemically.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Inflammation Mediators / metabolism
  • Injections, Intradermal
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Ligands
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Macaca mulatta / immunology
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism
  • Neutrophils / immunology
  • Oligodeoxyribonucleotides / pharmacology
  • Toll-Like Receptors / agonists*
  • Transcription, Genetic / drug effects


  • Adjuvants, Immunologic
  • CPG-oligonucleotide
  • Imidazoles
  • Inflammation Mediators
  • Ligands
  • Oligodeoxyribonucleotides
  • Toll-Like Receptors
  • resiquimod