Abstract

Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4 + T cells promoted the generation of Foxp3 + Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA-induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3 + Treg cells associated with enhanced levels of transforming growth factor-β production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3 + Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases.

Original languageEnglish
Pages (from-to)199-212
Number of pages14
JournalImmunology
Volume156
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

Fingerprint

Regulatory T-Lymphocytes
Adenoviridae
Dendritic Cells
Asthma
Ovalbumin
Ligands
T-Lymphocytes
Cell Death
Th2 Cells
Interleukin-13
Adoptive Transfer
Immune System Diseases
Interleukin-5
Transforming Growth Factors
Antigen-Presenting Cells
Immunosuppressive Agents
Coculture Techniques
Interleukin-4
Allergens
Immunoglobulin E

Keywords

  • asthma
  • dendritic cell
  • Jagged1
  • regulatory T cell
  • T helper type 2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{2ee4cde232c84a2e9f40738b3459b4ba,
title = "Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3 + regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice",
abstract = "Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4 + T cells promoted the generation of Foxp3 + Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA-induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3 + Treg cells associated with enhanced levels of transforming growth factor-β production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3 + Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases.",
keywords = "asthma, dendritic cell, Jagged1, regulatory T cell, T helper type 2",
author = "Lin, {Chu Lun} and Hsieh, {Chia Ling} and Huang, {Huei Mei} and Fan, {Chia Kwung} and Lee, {Yueh Lun}",
year = "2019",
month = "2",
day = "1",
doi = "10.1111/imm.13021",
language = "English",
volume = "156",
pages = "199--212",
journal = "Immunology",
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TY - JOUR

T1 - Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3 + regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice

AU - Lin, Chu Lun

AU - Hsieh, Chia Ling

AU - Huang, Huei Mei

AU - Fan, Chia Kwung

AU - Lee, Yueh Lun

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4 + T cells promoted the generation of Foxp3 + Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA-induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3 + Treg cells associated with enhanced levels of transforming growth factor-β production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3 + Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases.

AB - Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4 + T cells promoted the generation of Foxp3 + Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA-induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3 + Treg cells associated with enhanced levels of transforming growth factor-β production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3 + Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases.

KW - asthma

KW - dendritic cell

KW - Jagged1

KW - regulatory T cell

KW - T helper type 2

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U2 - 10.1111/imm.13021

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VL - 156

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