title: Configuration-dependent Presentation of Multivalent IL-15:IL-15Rα Enhances the Antigen-specific T Cell Response and Anti-tumor Immunity.
abstract: Here we report a "configuration-dependent" mechanism of action for IL-15:IL-15Rα (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15:IL-15Rα molecules are presented to target cells significantly affects its function as a vaccine adjuvant. Although the cellular mechanism of IL-15 trans-presentation via IL-15Rα and its importance for IL-15 function have been described, the full effect of the IL-15:IL-15Rα configuration on responding cells is not yet known. We found that trans-presenting IL-15:IL-15Rα in a multivalent fashion on the surface of antigen-encapsulating nanoparticles enhanced the ability of nanoparticle-treated dendritic cells (DCs) to stimulate antigen-specific CD8(+) T cell responses. Localization of multivalent IL-15:IL-15Rα and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15:IL-15Rα-coated nanoparticles displayed higher levels of functional IL-15 on the cell surface, implicating a mechanism for nanoparticle-mediated transfer of IL-15 to the DC surface. Using artificial antigen-presenting cells to highlight the effect of IL-15 configuration on DCs, we showed that artificial antigen-presenting cells presenting IL-15:IL-15Rα increased the sensitivity and magnitude of the T cell response, whereas IL-2 enhanced the T cell response only when delivered in a paracrine fashion. Therefore, the mode of cytokine presentation (configuration) is important for optimal immune responses. We tested the effect of configuration dependence in an aggressive model of murine melanoma and demonstrated significantly delayed tumor progression induced by IL-15:IL-15Rα-coated nanoparticles in comparison with monovalent IL-15:IL-15Rα. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15:IL-15Rα-coated nanoparticles for antigen delivery.
authors.affiliation: From the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511.
authors.forename: Enping
authors.initials: E
authors.lastname: Hong
authors.affiliation: From the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511.
authors.forename: Ilana M
authors.initials: IM
authors.lastname: Usiskin
authors.affiliation: the Vaccine Branch, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bergamaschi
authors.affiliation: Dermatology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hanlon
authors.affiliation: Dermatology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Edelson
authors.affiliation: the Department of Science, University of Copenhagen, Copenhagen 1017, Denmark.
authors.forename: Sune
authors.initials: S
authors.lastname: Justesen
authors.affiliation: the Vaccine Branch, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, and.
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
authors.affiliation: the Departments of Immunobiology and.
authors.forename: Richard A
authors.identifier: http://orcid.org/0000-0003-4461-0778
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: From the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, the Departments of Immunobiology and tarek.fahmy@yale.edu.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D020099:Coated Materials, Biocompatible / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D053647:Receptors, Interleukin-15 / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D020099:Coated Materials, Biocompatible; C569274:IL15 protein, human; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D053647:Receptors, Interleukin-15
keywords: CD8+ T cell; IL-15; IL-15 receptor α; T cell; antigen delivery; antigen presentation; dendritic cell; immunotherapy; nanoparticles; nanotechnology