Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines
| Autor: | Emily Carrow, Hirotaka Imai, Hani Rustom, M. Suresh, Brandon Neldner, Yoshihiro Kawaoka, Erin H. Plisch, David J. Gasper |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Physiology Acrylic Resins CD8-Positive T-Lymphocytes Pathology and Laboratory Medicine Mice 0302 clinical medicine Cognition Learning and Memory Spectrum Analysis Techniques Immune Physiology Cellular types Lecithins Cytotoxic T cell Public and Occupational Health Biology (General) Immune Response Respiratory Tract Infections Vaccines Microscopy Confocal Immune cells hemic and immune systems Flow Cytometry Vaccination and Immunization Adoptive Transfer 3. Good health Vaccination Spectrophotometry Influenza A virus Influenza Vaccines White blood cells Cytophotometry Research Article Cell biology Blood cells QH301-705.5 Immunology T cells chemical and pharmacologic phenomena Cytotoxic T cells Mice Transgenic Biology Research and Analysis Methods Microbiology 03 medical and health sciences Immune system Signs and Symptoms Antigen Adjuvants Immunologic Orthomyxoviridae Infections Immunity Memory Diagnostic Medicine Virology Genetics Animals Molecular Biology Administration Intranasal Heterosubtypic immunity Medicine and health sciences Inflammation Biology and life sciences RC581-607 Mice Inbred C57BL CTL Disease Models Animal 030104 developmental biology Animal cells Humoral immunity Cognitive Science Parasitology Preventive Medicine Immunologic diseases. Allergy Spleen 030215 immunology Neuroscience T-Lymphocytes Cytotoxic |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 12, Iss 12, p e1006064 (2016) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting-cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naïve CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the respiratory tract. Author Summary Current respiratory-virus vaccines typically employ non-replicating antigens and rely solely on the generation of humoral responses for protection. Viruses such as influenza can mutate and escape these responses, thereby limiting immunity and necessitating revaccination. Cell-mediated immunity (CMI) could provide broader protection by targeting viral components that infrequently mutate, however non-replicating vaccines capable of inducing CMI are not available. Impediments to vaccine development include an incomplete understanding of the nature of protective respiratory CMI and a lack of vaccine adjuvants capable of eliciting CMI to non-replicating antigens. Using a mouse model, we characterized the protective immunity afforded by CMI responses to non-replicating vaccines formulated with the adjuvant Adjuplex. We found that vaccination via either the subcutaneous or intranasal route was capable of inducing potent CMI responses. However, only intranasal vaccination protected against challenge with heterosubtypic influenza viruses. This protection correlated with enhancement of T cells with a resident-memory phenotype in the lungs. Additionally, mechanistic studies showed that Adjuplex affects antigen-presenting cells via activation and alteration of antigen uptake, processing, and presentation. The current studies: (1) identified an adjuvant that elicits protective CMI to respiratory viral pathogens; (2) suggested that stimulation of protective CMI in the respiratory tract requires intranasal vaccine delivery. |
| Databáze: | OpenAIRE |
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