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¹ Department of Microbiology and Immunology, and ² Department of Surgery, Dartmouth Medical School, Lebanon, NH 03756
³ Department of Pharmacology, 3M Pharmaceuticals, St. Paul, MN 55144

Address correspondence to Ross M. Kedl, 3M Pharmaceuticals, 3M Center, Bldg. 270-02-S-06, St. Paul, MN 55144. Phone: (651) 733-4821; Fax: (651) 737-5886; email: rmkedl{at}mmm.com

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) 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, IFN, 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.

Key Words: Toll like receptor • TLR7 • CD40 • CD8 • T cell

Abbreviations used in this paper: IRM, immune response modifier; TLR, Toll-like receptor.

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