Abstract
Respiratory syncytial virus (RSV) is one of the main pathogens associated with lower respiratory tract infections in infants and young children worldwide. Exosomes secreted by antigen presenting cells (APCs) can elicit immune responses by carrying major histocompatibility complex (MHC) class I molecules complexed with antigenic peptides and other co-stimulating factors. Therefore, we developed novel immunomagnetic nanographene particles to sequentially isolate, surface engineer, and release intact dendritic cell (DC) exosomes for use as a potential vaccine platform against RSV. The H-2Db-restricted, immunodominant peptides from RSV (M187–195 and NS161–75) were introduced to MHC-I on DC-derived exosomes to express peptide/MHC-I (pMHC-I) complexes. A mouse model of RSV infection was used to define the immunogenicity of surface engineered exosomes for activating virus-specific immune responses. Ex vivo assays demonstrated that engineered exosomes carrying RSV-specific peptides can elicit interferon-gamma (IFN-γ) production by virus-specific CD8+ T cells isolated from RSV-infected C57BL/6 mice. In vivo assays demonstrated that subcutaneous administration of both M187–195 and NS161–75 engineered exosomes to mice, with or without additional adjuvant, appeared safe and well tolerated, however, did not prime antigen-specific CD8+ T cell responses. Surface engineered exosomes are immunogenic and promising for further development as a vaccine platform.
Highlights
Respiratory syncytial virus (RSV) is one of the main pathogens associated with lower respiratory tract infections in infants and young children worldwide
Immature dendritic cell (DC) maintain T cell tolerance, whereas mature DCs have a higher number of peptide/major histocompatibility complex (MHC) complexes and costimulatory molecules such as CD40 and CD80/86 interacting with CD40 ligand and CD28, respectively, on the T cell, rendering them highly effective at inducing T cell responses[10]
Due to the positive charge property of M187–195 peptide and the negative charge property of NS161–75 peptide, such zeta potential changes indicate the successful surface engineering of DC exosomes with RSV-specific peptides (Fig. 1E)
Summary
Respiratory syncytial virus (RSV) is one of the main pathogens associated with lower respiratory tract infections in infants and young children worldwide. Exosomes secreted by antigen presenting cells (APCs) can elicit immune responses by carrying major histocompatibility complex (MHC) class I molecules complexed with antigenic peptides and other co-stimulating factors. We developed novel immunomagnetic nanographene particles to sequentially isolate, surface engineer, and release intact dendritic cell (DC) exosomes for use as a potential vaccine platform against RSV. Ex vivo assays demonstrated that engineered exosomes carrying RSVspecific peptides can elicit interferon-gamma (IFN-γ) production by virus-specific CD8+ T cells isolated from RSV-infected C57BL/6 mice. Exosomes derived from DCs of male mice with functional pMHC complexes are able to elicit responses from naïve, transgenic, male-antigen-specific CD4+ T cells both in vivo and in vitro[12]. It has been reported that exosomes secreted by virus-infected cells can elicit immune responses due to carrying viral-specific proteins and R NAs13. Due to the innate immunogenicity and safety and evident importance in cell signaling in vivo, an exosome-based vaccine has gained significant interest in aspects of research and clinical application
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