Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells

Eur J Immunol. 2003 Jun;33(6):1633-41. doi: 10.1002/eji.200323813.


Two different types of CpG motif-containing oligonucleotides (CpG ODN) have been described: CpG-A with high induction of IFN-alpha in plasmacytoid dendritic cells; and CpG-B with little induction of IFN-alpha, but potent activation of B cells. In this study, we demonstrate that CpG-A fail to activate B cells unless plasmacytoid dendritic cells are present. We identified a new set of CpG ODN sequences which induces high levels of IFN-alpha in plasmacytoid dendritic cells but remains capable of directly activating B cells. These new CpG ODN (termed CpG-C) are more potent stimulants of B cells than CpG-B due to their ability of directly and indirectly (via plasmacytoid dendritic cells) activating B cells. The sequence of CpG-C combines structural elements of both CpG-A and CpG-B. The most potent sequence, M362, contains a 5'-end 'TCGTCG-motif' and a 'GTCGTT-motif', both of which are present in CpG-B (ODN 2006); a palindromic sequence characteristic for CpG-A (ODN 2216); but no poly G motif required for CpG-A. In conclusion, we defined the first CpG-containing sequences that potently activate both TLR9-expressing immune cell subsets in humans, the plasmacytoid dendritic cell and the B cell. CpG-C may allow for improved therapeutic immuno-modulation in vivo.

Publication types

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

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Adult
  • Aged
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology
  • B7-2 Antigen
  • Base Sequence
  • CpG Islands / immunology*
  • DNA-Binding Proteins / physiology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dose-Response Relationship, Immunologic
  • Drug Design
  • Gene Expression Regulation / drug effects*
  • Humans
  • Interferon-alpha / biosynthesis*
  • Interferon-alpha / genetics
  • Lymphocyte Activation / drug effects*
  • Male
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Middle Aged
  • Oligodeoxyribonucleotides / chemistry
  • Oligodeoxyribonucleotides / immunology*
  • Oligodeoxyribonucleotides / pharmacology
  • Receptors, Cell Surface / physiology
  • Structure-Activity Relationship
  • Toll-Like Receptor 9


  • Adjuvants, Immunologic
  • Antigens, CD
  • B7-2 Antigen
  • CD86 protein, human
  • CPG-oligonucleotide
  • DNA-Binding Proteins
  • Interferon-alpha
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • Receptors, Cell Surface
  • TLR9 protein, human
  • Toll-Like Receptor 9