Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN

J Exp Med. 2004 Mar 15;199(6):775-84. doi: 10.1084/jem.20031591. Epub 2004 Mar 8.


Toll-like receptors are important in the activation of innate immunity, and CD40 is a molecule critical for many T and B cell responses. Whereas agonists for either pathway have been used as vaccine adjuvants, we show that a combination of Toll-like receptor (TLR)7 and CD40 agonists synergize to stimulate CD8+ T cell responses 10-20-fold greater than the use of either agonist alone. Antigen-specific CD8+ T cells elicited from combination CD40/TLR7 treatment demonstrated both lytic activities and interferon (IFN)gamma production and an enhanced secondary response to antigenic challenge. Agonists for TLRs 2/6, 3, 4, and 9 also synergized with CD40 stimulation, demonstrating that synergy with the CD40 pathway is a property of TLR-derived stimuli in general. The CD8+ T cell expansion induced by CD40/TLR7 triggering was independent of CD4+ T cells, IFNgamma, and IL-12 but dependent on B7-mediated costimulation and surprisingly on type I IFN. These studies provide the rational basis for the use of TLR and CD40 agonists together as essential adjuvants to optimize vaccines designed to elicit protective or therapeutic immunity.

Publication types

  • Comparative Study

MeSH terms

  • Adjuvants, Immunologic / metabolism*
  • Aminoquinolines / pharmacology*
  • Animals
  • Antibodies, Monoclonal
  • CD40 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytotoxicity Tests, Immunologic
  • Female
  • Flow Cytometry
  • Immunity, Innate / drug effects*
  • Immunization
  • Interferon Type I / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Major Histocompatibility Complex / immunology
  • Membrane Glycoproteins / agonists*
  • Mice
  • Mice, Inbred C57BL
  • Ovalbumin
  • Receptors, Cell Surface / agonists*
  • Signal Transduction / immunology*
  • Toll-Like Receptor 7
  • Toll-Like Receptors
  • Vaccines / immunology*


  • 4-amino-alpha,alpha,2-trimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol
  • Adjuvants, Immunologic
  • Aminoquinolines
  • Antibodies, Monoclonal
  • CD40 Antigens
  • Interferon Type I
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Toll-Like Receptor 7
  • Toll-Like Receptors
  • Vaccines
  • Interferon-gamma
  • Ovalbumin