title: TLR agonists are highly effective at eliciting functional memory CTLs of effector memory phenotype in peptide immunization.
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 in mice. Peptide boosting with lipopolysaccharide (LPS), a TLR4-ligand, has been shown to progressively enhance memory 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 of memory 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.
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Smyth
authors.forename: Karla
authors.initials: K
authors.lastname: Garcia
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Sun
authors.forename: Wenbin
authors.initials: W
authors.lastname: Tuo
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000818:Animals; D018899:CpG Islands; D007114:Immunization; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000276:immunology*; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000819:agonists*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D009842:Oligopeptides; C519703:TLR3 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011070:Poly I-C