Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

Yoshiko Fukuyama; Daisuke Tokuhara; Shinichi Sekine; Kosuke Kataoka; Jonathan D. Markham; Allyson R. Irwin; Grace H. Moon; Yuka Tokuhara; Keiko Fujihashi; Julia Davydova; Masato Yamamoto; Rebekah S. Gilbert; Kohtaro Fujihashi

doi:10.1016/j.bbrc.2011.12.046

Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

Yoshiko Fukuyama, Daisuke Tokuhara, Shinichi Sekine, Kosuke Kataoka, Jonathan D. Markham, Allyson R. Irwin, Grace H. Moon, Yuka Tokuhara, Keiko Fujihashi, Julia Davydova, Masato Yamamoto, Rebekah S. Gilbert, Kohtaro Fujihashi

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Abstract

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.

Original language	English (US)
Pages (from-to)	6-11
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	418
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2011.12.046
State	Published - Feb 3 2012

Bibliographical note

Funding Information:
We thank Dr. Jerry R. McGhee for his scientific discussions regarding these experiments. This work is supported by National Institutes of Health (NIH) Grants DE012242 , AG025873 and CA094084 as well as the Japan Society of the Promotion of Science (JSPS) program entitled “Young Researcher Overseas Visits Program for Vitalizing Brain Circulation”, the Japan Foundation for Pediatric Research and Houjinkai Fellowship Award of the Department of Pediatrics at Osaka City University Graduate School of Medicine and The Mochida Memorial Foundation for Medical and Pharmaceutical Research .

Keywords

Cytokines
Dendritic cells
Notch ligands

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Fukuyama, Y., Tokuhara, D., Sekine, S., Kataoka, K., Markham, J. D., Irwin, A. R., Moon, G. H., Tokuhara, Y., Fujihashi, K., Davydova, J., Yamamoto, M., Gilbert, R. S., & Fujihashi, K. (2012). Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses. Biochemical and Biophysical Research Communications, 418(1), 6-11. https://doi.org/10.1016/j.bbrc.2011.12.046

Fukuyama, Y, Tokuhara, D, Sekine, S, Kataoka, K, Markham, JD, Irwin, AR, Moon, GH, Tokuhara, Y, Fujihashi, K, Davydova, J , Yamamoto, M, Gilbert, RS & Fujihashi, K 2012, 'Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses', Biochemical and Biophysical Research Communications, vol. 418, no. 1, pp. 6-11. https://doi.org/10.1016/j.bbrc.2011.12.046

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abstract = "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.",

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AU - Tokuhara, Daisuke

AU - Sekine, Shinichi

AU - Kataoka, Kosuke

AU - Markham, Jonathan D.

AU - Irwin, Allyson R.

AU - Moon, Grace H.

AU - Tokuhara, Yuka

AU - Fujihashi, Keiko

AU - Davydova, Julia

AU - Yamamoto, Masato

AU - Gilbert, Rebekah S.

AU - Fujihashi, Kohtaro

N1 - Funding Information: We thank Dr. Jerry R. McGhee for his scientific discussions regarding these experiments. This work is supported by National Institutes of Health (NIH) Grants DE012242 , AG025873 and CA094084 as well as the Japan Society of the Promotion of Science (JSPS) program entitled “Young Researcher Overseas Visits Program for Vitalizing Brain Circulation”, the Japan Foundation for Pediatric Research and Houjinkai Fellowship Award of the Department of Pediatrics at Osaka City University Graduate School of Medicine and The Mochida Memorial Foundation for Medical and Pharmaceutical Research .

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N2 - 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.

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Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

Abstract

Bibliographical note

Keywords

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