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 February 1, 2010; First published January 25, 2010
Citation Information: J Clin Invest. 2010;120(2):607-616. https://doi.org/10.1172/JCI39293.
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Categories: 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 6

The triple–TLR ligand–treated DCs prevent expansion of Treg cells and exhibit minimal upregulation of PD-L1.

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The triple–TLR ligand–treated DCs prevent expansion of Treg cells and ex...
BM-DCs were treated with TLR ligands for 20 hours, and excess TLR ligands were removed. (A and B) Freshly isolated syngeneic splenic T cells were cocultured with TLR ligand–pretreated DCs. Foxp3+CD4+ cells were evaluated at 24 hours and 48 hours, respectively. Numbers indicate percentage of CD4+ T cells positive for Foxp3. (B) BM-DCs were treated with TLR ligands for 20 hours and stained with either anti-CD86 or anti–PD-L1 mAbs to measure levels of the costimulatory molecules. The experiments were repeated twice with similar results. *P < 0.05; **P < 0.01. Results are shown as mean ± SEM.