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TLR ligands are promising candidates for the development of novel vaccine adjuvants that can elicit protective immunity against emerging infectious diseases. Adjuvants have been used most frequently to increase the quantity of an immune response. However, the quality of a T cell response can be more important than its quantity. Stimulating certain pairs of TLRs induces a synergistic response in terms of activating dendritic cells and eliciting/enhancing T cell responses through clonal expansion, which increases the number of responding T cells. Here, we have found that utilizing ligands for 3 TLRs (TLR2/6, TLR3, and TLR9) greatly increased the protective efficacy of vaccination with an HIV envelope peptide in mice when compared with using ligands for only any 2 of these TLRs; surprisingly, increased protection was induced without a marked increase in the number of peptide-specific T cells. Rather, the combination of these 3 TLR ligands augmented the quality of the T cell responses primarily by amplifying their functional avidity for the antigen, which was necessary for clearance of virus. The triple combination increased production of DC IL-15 along with its receptor, IL-15Rα, which contributed to high avidity, and decreased expression of programmed death-ligand 1 and induction of Tregs. Therefore, selective TLR ligand combinations can increase protective efficacy by increasing the quality rather than the quantity of T cell responses.
Introduction
There has been an increasing global threat by the recent emergence of many viral infectious diseases, including HlV/ AIDS, avian influenza, SARS, Ebola, and West Nile virus. Vaccination promises to be an effective means to provide protection and control such diseases. Live microorganisms containing protective antigens have been shown to produce high vaccine efficacy, but meanwhile, the organisms used can be harmful to the host, as most of them were originally pathogenic. Since it is the microbial components that boost vaccine responses, using the fewest of them that can generate near equivalent efficacy would be more advantageous and less risky in immune activation.
A host recognizes microorganisms through its pattern recognition receptors by specifically interacting with highly conserved constituent microbial components. TLRs are an important of these receptors, widely expressed by various immune cells and able to induce immune responses by way of sensing different types of microbial invasion (1,2). DCs are among the...