Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice
Qing Zhu, … , Dennis M. Klinman, Jay A. Berzofsky
Qing Zhu, … , Dennis M. Klinman, Jay A. Berzofsky
Published January 25, 2010
Citation Information: J Clin Invest. 2010;120(2):607-616. https://doi.org/10.1172/JCI39293.
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Research Article Immunology

Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice

Abstract

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.

Authors

Qing Zhu, Colt Egelston, Susan Gagnon, Yongjun Sui, Igor M. Belyakov, Dennis M. Klinman, Jay A. Berzofsky

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Figure 1

TLR ligands in a triple combination in a peptide vaccine can markedly reduce viral load after virus challenge.

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TLR ligands in a triple combination in a peptide vaccine can markedly re...
(A) BALB/c mice were primed and boosted 3 weeks apart with an HIV Env peptide vaccine together with MALP2+poly(I:C)+CpG by the i.c.r. route (see details in Methods). Four months later, immunized animals were challenged i.c.r. with vPE16, and after 6 days, paired ovaries were recovered for virus titration with a plaque forming assay. One of 2 independent experiments with similar results is shown. Asterisk indicates the difference between groups (*P < 0.05; **P < 0.01; ***P < 0.001; n = 5). TLR ligand combination group is significantly different from all other groups. (B) Induction of antigen-specific (tetramer+) T cells in the draining popliteal LNs after s.c. immunization in the footpad with PCLUS3-18IIIB and TLR ligands. LN cells were recovered at 5 days and enumerated by staining for tetramer and intracellular IFN-γ. Results represent 1 of 2 independent experiments. tet, tetramer. Results are shown as mean ± SEM.