title: Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets.
abstract: The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4+ and CD8+ T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8-DEC205+CD103-CD326- langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8+ T cells as CD11c+CD8+ DCs. Moreover, these cells also influenced Th1 CD4+ T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines.
authors.affiliation: Vaccine Research Center and Cellular Immunology Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kastenmüller
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wille-Reece
authors.forename: Ross W B
authors.initials: RW
authors.lastname: Lindsay
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Trager
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Flynn
authors.forename: Maria R
authors.initials: MR
authors.lastname: Becker
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.forename: Botond Z
authors.initials: BZ
authors.lastname: Igyarto
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Kaplan
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kastenmüller
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002465:Cell Movement; D003713:Dendritic Cells / Q000166:cytology*; D007370:Interferon Type I / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D000941:Antigens; D015703:Antigens, CD; D039521:CD11c Antigen; C093569:DEC-205 receptor; D007370:Interferon Type I; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8