title: Priming CD8+ T cells with dendritic cells matured using TLR4 and TLR7/8 ligands together enhances generation of CD8+ T cells retaining CD28.
abstract: TLRs expressed on dendritic cells (DCs) differentially activate DCs when activated alone or in combination, inducing distinct cytokines and costimulatory molecules that influence T-cell responses. Defining the requirements of DCs to program T cells during priming to become memory rather than effector cells could enhance vaccine development. We used an in vitro system to assess the influence of DC maturation signals on priming naive human CD8+ T cells. Maturation of DCs with lipopolysaccharide (LPS; TLR4) concurrently with R848 (TLR7/8) induced a heterogeneous population of DCs that produced high levels of IL12 p70. Compared with DCs matured with LPS or R848 alone, the DC population matured with both adjuvants primed CD8+ T-cell responses containing an increased proportion of antigen-specific T cells retaining CD28 expression. Priming with a homogenous subpopulation of LPS/R848-matured DCs that were CD83(Hi)/CD80+/CD86+ reduced this CD28+ subpopulation and induced T cells with an effector cytokine signature, whereas priming with the less mature subpopulations of DCs resulted in minimal T-cell expansion. These results suggest that TLR4 and TLR7/8 signals together induce DCs with fully mature and less mature phenotypes that are both required to more efficiently prime CD8+ T cells with qualities associated with memory T cells.
authors.affiliation: Department of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle, WA 98109, USA. jpufnock@fhcrc.org
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Pufnock
authors.forename: Melinda
authors.initials: M
authors.lastname: Cigal
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Rolczynski
authors.forename: Erica
authors.initials: E
authors.lastname: Andersen-Nissen
authors.forename: Mathias
authors.initials: M
authors.lastname: Wolfl
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects / Q000502:physiology; D018106:CD28 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D004338:Drug Combinations; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007156:Immunologic Memory / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
chemical_list: D018106:CD28 Antigens; D004338:Drug Combinations; D007093:Imidazoles; D008024:Ligands; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C402365:resiquimod