Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (44), p.E989-E997
• Main Authors: Nembrini, Chiara, Stano, Armando, Dane, Karen Y, Ballester, Marie, van der Vlies, André J, Marsland, Benjamin J, Swartz, Melody A, Hubbell, Jeffrey A
• Format: Article
• Language: English
• Subjects: Animals; Antigen presentation; antigens; Antigens - immunology; bacteria; Biological Sciences; CD4 antigen; CD4-positive T-lymphocytes; CD8 antigen; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; Coculture Techniques; Conjugation; CpG islands; Cytokines; Cytotoxicity; Dendritic cells; Effector cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; gamma -Interferon; Helper cells; immune response; Immunization; Immunologic Memory; Immunological memory; Infection; interferon-gamma; Lung - immunology; Lung diseases; Lung Diseases - immunology; Lung Diseases - prevention & control; Lungs; lymph; Lymph nodes; Lymphocytes T; Memory cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morbidity; Mucosa; Nanoparticles; ova; Ovalbumin; Pathogens; PNAS Plus; respiratory tract diseases; Spleen; subunit vaccines; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; vaccination; Vaccines; Vaccines - administration & dosage; Vaccines - immunology; viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1104264108

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.