title: Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination.
abstract: The ability of vaccines to induce memory cytotoxic T-cell responses in the lung is crucial in stemming and treating pulmonary diseases caused by viruses and bacteria. However, most approaches to subunit vaccines produce primarily humoral and only to a lesser extent cellular immune responses. We developed a nanoparticle (NP)-based carrier that, upon delivery to the lung, specifically targets pulmonary dendritic cells, thus enhancing antigen uptake and transport to the draining lymph node; antigen coupling via a disulfide link promotes highly efficient cross-presentation after uptake, inducing potent protective mucosal and systemic CD8(+) T-cell immunity. Pulmonary immunization with NP-conjugated ovalbumin (NP-ova) with CpG induced a threefold enhancement of splenic antigen-specific CD8(+) T cells displaying increased CD107a expression and IFN-γ production compared with immunization with soluble (i.e., unconjugated) ova with CpG. This enhanced response was accompanied by a potent Th17 cytokine profile in CD4(+) T cells. After 50 d, NP-ova and CpG also led to substantial enhancements in memory CD8(+) T-cell effector functions. Importantly, pulmonary vaccination with NP-ova and CpG induced as much as 10-fold increased frequencies of antigen-specific effector CD8(+) T cells to the lung and completely protected mice from morbidity following influenza-ova infection. Here, we highlight recruitment to the lung of a long-lasting pool of protective effector memory cytotoxic T-cells by our disulfide-linked antigen-conjugated NP formulation. These results suggest the reduction-reversible NP system is a highly promising platform for vaccines specifically targeting intracellular pathogens infecting the lung.
authors.affiliation: Laboratory for Regenerative Medicine and Pharmacobiology, Institute of Bioengineering, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Nembrini
authors.forename: Armando
authors.initials: A
authors.lastname: Stano
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Dane
authors.forename: Marie
authors.initials: M
authors.lastname: Ballester
authors.forename: André J
authors.initials: AJ
authors.lastname: van der Vlies
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Marsland
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007156:Immunologic Memory; D008168:Lung / Q000276:immunology*; D008171:Lung Diseases / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014612:Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000941:Antigens; D014612:Vaccines