Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN

CL Ahonen, CL Doxsee, SM McGurran… - The Journal of …, 2004 - rupress.org
CL Ahonen, CL Doxsee, SM McGurran, TR Riter, WF Wade, RJ Barth, JP Vasilakos…
The Journal of experimental medicine, 2004rupress.org
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) γ production …
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)γ 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, IFNγ, 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.
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