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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR AND IMMUNOLOGICAL APPROACHES TO CONTROLLING GI NEMATODE INFECTIONS OF RUMINANTS

Location: Animal Parasitic Diseases

Title: TLR agonists are highly effective at eliciting functional memory CTLs of effector memory phenotype in peptide immunization

Authors
item Smyth, K -
item Garcia, K -
item Sun, Z -
item Tuo, Wenbin
item Xiao, Z -

Submitted to: International Immunopharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 18, 2012
Publication Date: November 14, 2012
Citation: Smyth, K., Garcia, K., Sun, Z., Tuo, W., Xiao, Z. 2012. TLR agonists are highly effective at eliciting functional memory CTLs of effector memory phenotype in peptide immunization. International Immunopharmacology. 15:67-72.

Interpretive Summary: Tumor cells and cells infected with viruses can be eliminated by killer T cells. We have developed a novel approach using synthetic peptides and Toll-like receptor ligands that protects mice from infection by stimulating such killer T cells. The ability to produce such protection was previously demonstrated when a potent, bacterial-derived Toll-like receptor-4 ligand, ipopolyscaccharide, was used. To evaluate whether ligands to other Toll-like receptors have a similar effect, we determined the functions of Toll-like receptor-3 and -9 ligands, Poly IC and CpG, respectively, in the present study. Large numbers of killer T cells were stimulated with three injections. The results demonstrate that Toll-like receptor ligands are effective adjuvants in vaccination to generate functional killer T cells. These results will be useful in facilitating the development of vaccines and adjuvants for livestock against pathogens that require killer T cells for protection. This work will benefit the livestock industry.

Technical Abstract: Given the importance of memory cytotoxic T lymphocytes (CTLs) in eliminating altered self-cells, including virus-infected and tumor cells, devising effective vaccination strategies for generating memory CTLs is a priority in the field of immunology. Herein, we elaborate upon a novel boosting approach that utilizes synthetic peptides and Toll-like receptor (TLR) agonists as adjuvants to generate sufficient numbers of memory CTLs to protect against infection inmice. Peptide boostingwith lipopolysaccharide (LPS), a TLR4-ligand, has been shown to progressively enhancememory CTLs. Whether this result is strictly dependent on activation of TLR4 or can be similarly achieved by signaling through other TLRs is of practical interest in vaccine development but is yet unknown. In this report, we present evidence that intravenous peptide boosting together with TLR3 and TLR9 agonists (Poly IC and CpG, respectively) is highly effective and induces large quantities ofmemory CTLs of effector memory phenotype after three boosts. Compared to LPS, CpG and Poly IC generate more robust immune responses after the first and second boosts, indicating that a protective level of CTLs might be achieved with fewer boosts when CpG or Poly IC is used. Lastly, the resultant memory CTLs from boosting with different TLR agonists as adjuvant are equally protective against pathogen challenge and are not immune senescent. Therefore, TLR agonists are effective adjuvants in intravenous peptide boosting for the generation of functional memory CTLs.

Last Modified: 10/22/2014
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