Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses

J Immunol. 2003 Oct 15;171(8):4320-8. doi: 10.4049/jimmunol.171.8.4320.

Abstract

Optimal Ag targeting and activation of APCs, especially dendritic cells (DCs), are important in vaccine development. In this study, we report the effects of different Toll-like receptor (TLR)-binding compounds to enhance immune responses induced by human APCs, including CD123(+) plasmacytoid DCs (PDCs), CD11c(+) myeloid DCs (MDCs), monocytes, and B cells. PDCs, which express TLR7 and TLR9, responded to imidazoquinolines (imiquimod and R-848) and to CpG oligodeoxynucleotides stimulation, resulting in enhancement in expression of costimulatory molecules and induction of IFN-alpha and IL-12p70. In contrast, MDCs, which express TLR3, TLR4, and TLR7, responded to poly(I:C), LPS, and imidazoquinolines with phenotypic maturation and high production of IL-12 p70 without producing detectable IFN-alpha. Optimally TLR ligand-stimulated PDCs or MDCs exposed to CMV or HIV-1 Ags enhanced autologous CMV- and HIV-1-specific memory T cell responses as measured by effector cytokine production compared with TLR ligand-activated monocytes and B cells or unstimulated PDCs and MDCs. Together, these data show that targeting specific DC subsets using TLR ligands can enhance their ability to activate virus-specific T cells, providing information for the rational design of TLR ligands as adjuvants for vaccines or immune modulating therapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / metabolism*
  • Adjuvants, Immunologic / pharmacology
  • Antigen-Presenting Cells / classification
  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Differentiation / immunology
  • Cells, Cultured
  • CpG Islands / immunology
  • Cytomegalovirus / immunology*
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Epitopes, T-Lymphocyte / immunology
  • HIV-1 / immunology*
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Interferon-alpha / biosynthesis
  • Interleukin-12 / biosynthesis
  • Ligands
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / physiology
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Oligodeoxyribonucleotides / metabolism
  • Oligodeoxyribonucleotides / pharmacology
  • Poly I-C / metabolism
  • Poly I-C / pharmacology
  • Protein Subunits / biosynthesis
  • Receptors, Cell Surface / metabolism*
  • Receptors, Cell Surface / physiology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / virology
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors

Substances

  • Adjuvants, Immunologic
  • CPG-oligonucleotide
  • Epitopes, T-Lymphocyte
  • Imidazoles
  • Interferon-alpha
  • Ligands
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • Protein Subunits
  • Receptors, Cell Surface
  • TLR3 protein, human
  • TLR4 protein, human
  • TLR7 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Interleukin-12
  • Poly I-C
  • resiquimod