ABSTRACT
Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung.
Subject(s)
Allergens/immunology , Antigens, Dermatophagoides/immunology , Asthma/immunology , Dendritic Cells/immunology , Immunity, Cellular , Pyroglyphidae/immunology , Th2 Cells/immunology , Administration, Inhalation , Adoptive Transfer , Allergens/isolation & purification , Animals , Antigens, Dermatophagoides/administration & dosage , Antigens, Dermatophagoides/isolation & purification , Antigens, Ly/genetics , Antigens, Ly/immunology , Asthma/pathology , CD11b Antigen/genetics , CD11b Antigen/immunology , Cell Movement , Cell Proliferation , Dendritic Cells/transplantation , Gene Expression , Inflammation/immunology , Inflammation/pathology , Lung/immunology , Lung/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Mice , Mice, Transgenic , Monocytes/immunology , Monocytes/transplantation , Natural Cytotoxicity Triggering Receptor 1/genetics , Natural Cytotoxicity Triggering Receptor 1/immunology , Organ Specificity , Receptors, IgG/genetics , Receptors, IgG/immunologyABSTRACT
Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3(fl/fl)Cd11c-cre(+) mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly-features of systemic lupus erythematosus-and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.
Subject(s)
Cysteine Endopeptidases/metabolism , Dendritic Cells/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lupus Erythematosus, Systemic/immunology , Plasma Cells/metabolism , T-Lymphocytes/metabolism , Animals , Antibodies, Antinuclear/blood , Apoptosis/genetics , Autoimmunity/genetics , CD40 Ligand/metabolism , Cell Proliferation , Cells, Cultured , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/immunology , Dendritic Cells/immunology , Dendritic Cells/pathology , Humans , Interferon-gamma/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/immunology , Lupus Erythematosus, Systemic/blood , Mice , Mice, Mutant Strains , Mutation/genetics , Plasma Cells/immunology , Plasma Cells/pathology , RANK Ligand/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Tumor Necrosis Factor alpha-Induced Protein 3ABSTRACT
Dendritic cells (DCs) play a pivotal role in the regulation of the immune response. DC development and activation is finely orchestrated through transcriptional programs. GATA1 transcription factor is required for murine DC development, and data suggest that it might be involved in the fine-tuning of the life span and function of activated DCs. We generated DC-specific Gata1 knockout mice (Gata1-KODC), which presented a 20% reduction of splenic DCs, partially explained by enhanced apoptosis. RNA sequencing analysis revealed a number of deregulated genes involved in cell survival, migration, and function. DC migration toward peripheral lymph nodes was impaired in Gata1-KODC mice. Migration assays performed in vitro showed that this defect was selective for CCL21, but not CCL19. Interestingly, we show that Gata1-KODC DCs have reduced polysialic acid levels on their surface, which is a known determinant for the proper migration of DCs toward CCL21.
Subject(s)
Cell Movement/immunology , Chemokine CCL21/immunology , Dendritic Cells/immunology , GATA1 Transcription Factor/immunology , Lymph Nodes/immunology , Sialic Acids/immunology , Animals , Cell Movement/genetics , Chemokine CCL19/genetics , Chemokine CCL19/immunology , Chemokine CCL21/genetics , Dendritic Cells/cytology , GATA1 Transcription Factor/deficiency , Lymph Nodes/cytology , Mice , Mice, Knockout , Sialic Acids/geneticsABSTRACT
Asthma is an inflammatory disease of the airways associated with a T helper (Th)2 response. Such a response in the lungs requires complex interactions between innate cells and structural cells. Dendritic cells (DCs) are pivotal during sensitization to allergens but clearly require epithelium-derived signals to become activated. Epithelial cells also contribute to the activation and the survival of mast cells (MCs), basophils, and eosinophils and group 2 innate lymphoid cells (ILC2s). In turn, these innate cells can activate DCs to sustain Th2 immunity. Here, we review the role played by these different populations of immune cells in the pathogenesis of asthma and how they interact to orchestrate Th2 immunity.
Subject(s)
Asthma/immunology , Immunity, Innate/immunology , Th2 Cells/immunology , Animals , Basophils/immunology , Dendritic Cells/immunology , Eosinophils/immunology , Humans , Lymphocytes/immunology , Mast Cells/immunologyABSTRACT
High mobility group box 1 (HMGB1) is a molecular alarm signal that triggers an immune response when released. It was assumed that the receptor for advanced glycation end-products (RAGE) would mediate the signal to the immune system. Recently pattern recognition receptors that are triggered by molecules of bacterial origin (the Toll-like receptor (TLR) family) were shown to also respond to HMGB1. Now two papers establish the TLR4-HMGB1 axis as proinflammatory, eventually leading to disparate conditions like seizures or skin cancer. These reports add a new twist to our understanding of the mode of action of the alarm signal HMGB1.