title: Critical role of TLR7 signaling in the priming of cross-protective cytotoxic T lymphocyte responses by a whole inactivated influenza virus vaccine.
abstract: Current influenza vaccines fail to induce protection against antigenically distinct virus strains. Accordingly, there is a need for the development of cross-protective vaccines. Previously, we and others have shown that vaccination with whole inactivated virus (WIV) induces cross-protective cellular immunity in mice. To probe the mechanistic basis for this finding, we investigated the role of TLR7, a receptor for single-stranded RNA, in induction of cross-protection. Vaccination of TLR7-/- mice with influenza WIV failed to protect against a lethal heterosubtypic challenge; in contrast, wild-type mice were fully protected. The lack of protection in TLR7-/- mice was associated with high viral load and a relative paucity of influenza-specific CD8+ cytotoxic T lymphocyte (CTL) responses. Dendritic cells (DCs) from TLR7-/- mice were unable to cross-present WIV-derived antigen to influenza-specific CTLs in vitro. Similarly, TLR7-/- DCs failed to mature and become activated in response to WIV, as determined by the assessment of surface marker expression and cytokine production. Plasmacytoid DCs (pDCs) derived from wild-type mice responded directly to WIV while purified conventional DCs (cDCs) did not respond to WIV in isolation, but were responsive in mixed pDC/cDC cultures. Depletion of pDCs prior to and during WIV immunization resulted in reduced numbers of influenza-specific CTLs and impaired protection from heterosubtypic challenge. Thus, TLR7 plays a critical role in the induction of cross-protective immunity upon vaccination with WIV. The initial target cells for WIV appear to be pDCs which by direct or indirect mechanisms promote activation of robust CTL responses against conserved influenza epitopes.
authors: Molecular Virology Section, Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Natalija
authors: N
authors: Budimir
authors: Aalzen
authors: A
authors: de Haan
authors: Tjarko
authors: T
authors: Meijerhof
authors: Simke
authors: S
authors: Waijer
authors: Louis
authors: L
authors: Boon
authors: Emma
authors: E
authors: Gostick
authors: David A
authors: DA
authors: Price
authors: Jan
authors: J
authors: Wilschut
authors: Anke
authors: A
authors: Huckriede
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D056738:Cross Protection / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004285:Dogs; D007114:Immunization; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D015398:Signal Transduction / Q000276:immunology*; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D015164:Vaccines, Inactivated / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D051199:Toll-Like Receptor 7; D015164:Vaccines, Inactivated; D014765:Viral Vaccines
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