Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses.
Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c(+) dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c(+) DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c(+) DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c(+) DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4(+) T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-γ, IL-2 and IL-4 producing CD4(+) T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch-Notch-L pathway. These results show that Ad-FL induces CD11c(+) DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.
Department of Pediatric Dentistry, The Immunobiology Vaccine Center, The Institute of Oral Health Research, The University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
Yoshiko
Y
Fukuyama
Daisuke
D
Tokuhara
Shinichi
S
Sekine
Kosuke
K
Kataoka
Jonathan D
JD
Markham
Allyson R
AR
Irwin
Grace H
GH
Moon
Yuka
Y
Tokuhara
Keiko
K
Fujihashi
Julia
J
Davydova
Masato
M
Yamamoto
Rebekah S
RS
Gilbert
Kohtaro
K
Fujihashi
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D039521:CD11c Antigen / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D007110:Immunity, Active; D018928:Immunity, Mucosal; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D000072101:Jagged-2 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000276:immunology; D051880:Receptors, Notch / Q000276:immunology*; D000072099:Serrate-Jagged Proteins; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D039521:CD11c Antigen; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C084881:flt3 ligand protein