title: Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T cell activation via IL-15-dependent DC crosstalk.
abstract: Most vaccines depend on coadministration of Ags and adjuvants that activate APCs. Nanoparticles (NPs) have emerged as an attractive vehicle for synchronized delivery of Ags and adjuvants to APCs and can be targeted to specific cell types, such as dendritic cells (DCs), which are potent APCs. Which subset of human DCs should be targeted for optimal activation of T cell immunity, however, remains unknown. In this article, we describe a poly-lactic-coglycolic acid-based NP platform, wherein avidin-decorated NPs can be targeted to multiple human DC subsets via biotinylated Abs. Both BDCA3(+) and monocyte-derived DC-SIGN(+) NP-loaded DCs were equally effective at generating Ag-specific human T cells in culture, including against complex peptide mixtures from viral and tumor Ags across multiple MHC molecules. Ab-mediated targeting of NPs to distinct DC subsets led to enhanced T cell immunity. However, combination targeting to both DC-SIGN and BDCA3(+) DCs led to significantly greater activation of T cells compared with targeting either DC subset alone. Enhanced T cell activation following combination targeting depended on DC-mediated cytokine release and was IL-15 dependent. These data demonstrate that simultaneous targeting of multiple DC subsets may improve NP vaccines by engaging DC crosstalk and provides a novel approach to improving vaccines against pathogens and tumors.
authors: Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT 06510; Department of Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510;
authors: Kartik
authors: K
authors: Sehgal
authors: Department of Biomedical Engineering, Yale School of Engineering, Yale University, New Haven, CT 06510;
authors: Ragy
authors: R
authors: Ragheb
authors: Department of Biomedical Engineering, Yale School of Engineering, Yale University, New Haven, CT 06510; Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510; and.
authors: Tarek M
authors: TM
authors: Fahmy
authors: Department of Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510; Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510; and Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06510.
authors: Madhav V
authors: MV
authors: Dhodapkar
authors: Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT 06510; Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06510 kavita.dhodapkar@yale.edu.
authors: Kavita M
authors: KM
authors: Dhodapkar
mesh_terms: D000954:Antigens, Surface / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D053758:Nanoparticles; D011956:Receptors, Cell Surface / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018180:Thrombomodulin; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D019409:Interleukin-15; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C569274:IL15 protein, human; C546931:THBD protein, human