ABSTRACT
Th1 and Th2 cells mutually antagonize each other's differentiation. Consequently, allergen-specific Th1 cells are believed to be able to suppress the development of Th2 cells and to prevent the development of atopic disorders. To determine whether a pre-existing Ag-specific Th1 response can affect the development of Th2 cells in vivo, we used an immunization model of Ag-pulsed murine dendritic cell (DC) transfer to induce distinct Th responses. When transferred into naive mice, Ag-pulsed CD8alpha(+) DCs induced a Th1 response and the production of IgG2a, whereas CD8alpha(-) DCs primed a Th2 response and the production of IgE. In the presence of a pre-existing Ag-specific Th2 environment due to Ag-pulsed CD8alpha(-) DC transfer, CD8alpha(+) DCs failed to prime Th1 cells. In contrast, CD8alpha(-) DCs could prime a Th2 response in the presence of a pre-existing Ag-specific Th1 environment. Moreover, exogenous IL-4 abolished the Th1-inducing potential of CD8alpha(+) DCs in vitro, but the addition of IFN-gamma did not effectively inhibit the potential of CD8alpha(-) DCs to prime IL-4-producing cells. Thus, Th1 and Th2 cells differ in their potential to inhibit the development of the other. This suggests that the early induction of allergen-specific Th1 cells before allergy sensitization will not prevent the development of atopic disorders.
Subject(s)
Cell Differentiation/immunology , Epitopes, T-Lymphocyte/immunology , Immunosuppression Therapy , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/cytology , Adoptive Transfer , Animals , CD8 Antigens/biosynthesis , Cell Communication/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dendritic Cells/transplantation , Growth Inhibitors/pharmacology , Growth Inhibitors/physiology , Immunoglobulin G/biosynthesis , Interferon-gamma/biosynthesis , Interferon-gamma/physiology , Interleukin-4/biosynthesis , Interleukin-4/pharmacology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Resting Phase, Cell Cycle/immunology , Spleen/cytology , Spleen/immunology , Spleen/metabolism , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Th1 Cells/cytology , Th2 Cells/immunology , Th2 Cells/metabolismABSTRACT
Dendritic cells (DCs) regulate the development of distinct Th populations and thereby provoke appropriate immune responses to various kinds of Ags. In the present work, we investigated the role CD40-CD154 interactions play during the process of Th cell priming by CD8 alpha(+) and CD8 alpha(-) murine DC subsets, which have been reported to differently regulate the Th response. Adoptive transfer of Ag-pulsed CD8 alpha(+) DCs induced a Th1 response and the production of IgG2a Abs, whereas transfer of CD8 alpha(-) DCs induced Th2 cells and IgE Abs in vivo. Induction of distinct Th populations by each DC subset was also confirmed in vitro. Although interruption of CD80/CD86-CD28 interactions inhibited Th cell priming by both DC subsets, disruption of CD40-CD154 interactions only inhibited the induction of the Th1 response by CD8 alpha(+) DCs in vivo. CD40-CD154 interactions were not required for the proliferation of Ag-specific naive Th cells stimulated by either DC subset, but were indispensable in the production of IL-12 from CD8 alpha(+) DCs and their induction of Th1 cells in vitro. Taken together, in our immunization model of Ag-pulsed DC transfer, CD40-CD154 interactions play an important role in the development of CD8 alpha(+) DC-driven Th1 responses but not CD8 alpha(-) DC-driven Th2 responses to protein Ags.
Subject(s)
CD40 Antigens/physiology , CD40 Ligand/physiology , CD8 Antigens/biosynthesis , Dendritic Cells/immunology , Dendritic Cells/metabolism , Lymphocyte Activation/immunology , Signal Transduction/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , CD40 Antigens/biosynthesis , CD40 Antigens/metabolism , CD40 Ligand/biosynthesis , CD40 Ligand/metabolism , CD8 Antigens/metabolism , Cell Division/immunology , Cells, Cultured , Cytokines , Dendritic Cells/transplantation , Immunophenotyping , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , Th1 Cells/immunologyABSTRACT
BACKGROUND: Since antigen-specific IgE and eosinophils are major inducing factors of allergic inflammation of the airways, both factors are therapeutic targets of asthma. We investigated the effects of ONO-4007, a nontoxic lipid A analogue, on antigen-specific antibody response and the recruitment of eosinophils into airways in murine systems. METHODS: BALB/c mice were injected ONO-4007 intraperitoneally during sensitization with ovalbumin (OVA) and aluminium hydroxide to determine its effects on the antigen-specific antibody response. ONO-4007 was also injected intravenously during either systemic sensitization and inhalation with OVA, or sensitization or inhalation alone to determine its effects on antigen-induced airway inflammation. In vitro effects of ONO-4007 on the functional differentiation of naive CD4+ T cells were investigated by culturing naive CD4+ T cells derived from DO11.10 mice and OVA-pulsed dendritic cells (CDCs) with ONO-4007. RESULTS: ONO-4007 inhibited antigen-specific IgE and IgG1, but not IgG2a responses. ONO-4007 decreased the recruitment of eosinophils and the levels of IL-5 in bronchoalveolar lavage fluid, not only when it was injected during systemic sensitization and inhalation with OVA, but also during inhalation alone. ONO-4007 inhibited the differentiation of IL-4- and IL-13-producing CD4+ T cells in vitro, which was partly mediated by DCs. CONCLUSIONS: ONO-4007 inhibited antigen-specific IgE and IgG1 responses and antigen-induced eosinophil recruitment into the airways in BALB/c mice. These effects were mediated, at least partly, by the modulation of DCs, although there may also be other mechanisms.
