A novel adenovirus expressing Flt3 ligand enhances mucosal immunity by inducing mature nasopharyngeal-associated lymphoreticular tissue dendritic cell migration.
Previously, we showed that nasal administration of a naked cDNA plasmid expressing Flt3 ligand (FL) cDNA (pFL) enhanced CD4(+) Th2-type, cytokine-mediated mucosal immunity and increased lymphoid-type dendritic cell (DC) numbers. In this study, we investigated whether targeting nasopharyngeal-associated lymphoreticular tissue (NALT) DCs by a different delivery mode of FL, i.e., an adenovirus (Ad) serotype 5 vector expressing FL (Ad-FL), would provide Ag-specific humoral and cell-mediated mucosal immunity. Nasal immunization of mice with OVA plus Ad-FL as mucosal adjuvant elicited high levels of OVA-specific Ab responses in external secretions and plasma as well as significant levels of OVA-specific CD4(+) T cell proliferative responses and OVA-induced IFN-gamma and IL-4 production in NALT, cervical lymph nodes, and spleen. We also observed higher levels of OVA-specific CTL responses in the spleen and cervical lymph nodes of mice given nasal OVA plus Ad-FL than in mice receiving OVA plus control Ad. Notably, the number of CD11b(+)CD11c(+) DCs expressing high levels of costimulatory molecules was preferentially increased. These DCs migrated from the NALT to mucosal effector lymphoid tissues. Taken together, these results suggest that the use of Ad-FL as a nasal adjuvant preferentially induces mature-type NALT CD11b(+)CD11c(+) DCs that migrate to effector sites for subsequent CD4(+) Th1- and Th2-type cytokine-mediated, Ag-specific Ab and CTL responses.
Sekine
Shinichi
S
Department of Pediatric Dentistry and Microbiology, Immunobiology Vaccine Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Kataoka
Kosuke
K
Fukuyama
Yoshiko
Y
Adachi
Yasuo
Y
Davydova
Julia
J
Yamamoto
Masato
M
Kobayashi
Ryoki
R
Fujihashi
Keiko
K
Suzuki
Hideaki
H
Curiel
David T
DT
Shizukuishi
Satoshi
S
McGhee
Jerry R
JR
Fujihashi
Kohtaro
K
D000256:Adenoviridae / Q000235:genetics*; D000276:Adjuvants, Immunologic / Q000235:genetics; D000281:Administration, Intranasal; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology* / Q000821:virology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012157:Mononuclear Phagocyte System / Q000166:cytology / Q000276:immunology* / Q000821:virology; D009305:Nasopharynx / Q000166:cytology / Q000276:immunology* / Q000821:virology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D008565:Membrane Proteins; C084881:flt3 ligand protein; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3