RESUMO
Sublingual allergen immunotherapy (SLIT) is an emerging treatment option for allergic asthma and a potential disease-modifying strategy for asthma prevention. The key cellular events leading to such long-term tolerance remain to be fully elucidated. We administered prophylactic SLIT in a mouse model of house dust mite (HDM)-driven allergic asthma. HDM extract was sublingually administered over 3 weeks followed by intratracheal sensitization and intranasal challenges with HDM. Prophylactic SLIT prevented allergic airway inflammation and hyperreactivity with a low lab-to-lab variation. The HDM-specific T helper (Th)2 (cluster of differentiation 4 Th) response was shifted by SLIT toward a regulatory and Th17 response in the lung and mediastinal lymph node. By using Derp1-specific cluster of differentiation 4+ T cells (1-DER), we found that SLIT blocked 1-DER T cell recruitment to the mediastinal lymph node and dampened IL-4 secretion following intratracheal HDM sensitization. Sublingually administered Derp1 protein activated 1-DER T cells in the cervical lymph node via chemokine receptor7+ migratory dendritic cells (DC). DCs migrating from the oral submucosa to the cervical lymph node after SLIT-induced Foxp3+ regulatory T cells. When mice were sensitized with HDM, prior prophylactic SLIT increased Derp1 specific regulatory T cells (Tregs) and lowered Th2 recruitment in the lung. By using Foxp3-diphtheria toxin receptor mice, Tregs were found to contribute to the immunoregulatory prophylactic effect of SLIT on type 2 immunity. These findings in a mouse model suggest that DC-mediated functional Treg induction in oral mucosa draining lymph nodes is one of the driving mechanisms behind the disease-modifying effect of prophylactic SLIT.
Assuntos
Antígenos de Dermatophagoides , Asma , Células Dendríticas , Modelos Animais de Doenças , Fatores de Transcrição Forkhead , Pyroglyphidae , Imunoterapia Sublingual , Linfócitos T Reguladores , Células Th2 , Animais , Linfócitos T Reguladores/imunologia , Células Dendríticas/imunologia , Camundongos , Pyroglyphidae/imunologia , Fatores de Transcrição Forkhead/metabolismo , Antígenos de Dermatophagoides/imunologia , Asma/imunologia , Asma/terapia , Asma/prevenção & controle , Imunoterapia Sublingual/métodos , Células Th2/imunologia , Proteínas de Artrópodes/imunologia , Feminino , Alérgenos/imunologia , Alérgenos/administração & dosagem , Camundongos Endogâmicos BALB C , Humanos , Dessensibilização Imunológica/métodos , Cisteína Endopeptidases/imunologia , Cisteína Endopeptidases/metabolismoRESUMO
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
Assuntos
Plasticidade Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunidade , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções por Respirovirus/etiologia , Apresentação de Antígeno , Biomarcadores , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Imunofenotipagem , Interferon Tipo I/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/imunologia , Receptores Fc/metabolismo , Infecções por Respirovirus/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fatores de Transcrição , Viroses/genética , Viroses/imunologia , Viroses/metabolismo , Viroses/virologiaRESUMO
Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1 (-/-) mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1ß. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r (-/-) mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α-IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD.
RESUMO
Viral infections are a common cause of acute respiratory disease. The clinical course of infection and symptoms depend on the viral strain, the health status of the host, and the immunological status of the host. Dendritic cells (DCs) play a crucial role in recognizing and presenting viral antigens and in inducing adaptive immune responses that clear the virus. Because the lung is continuously exposed to the air, the lung is equipped with an elaborate network of DCs to sense incoming foreign pathogens. Increasing knowledge on DC biology has informed us that DCs are not a single cell type. In the steady state lung, three DC subsets can be defined: CD11b(+) or CD103(+) conventional DCs and plasmacytoid DCs. Upon inflammation, inflammatory monocyte-derived DCs are recruited to the lung. It is only recently that tools became available to allow DC subsets to be clearly studied. This review focuses on the activation of DCs and the function of lung DCs in the context of respiratory virus infection and highlights some cautionary points for interpreting older experiments.
Assuntos
Células Dendríticas/imunologia , Pulmão/imunologia , Pulmão/virologia , Viroses/imunologia , Vírus/imunologia , Animais , Células Dendríticas/metabolismo , Humanos , Pulmão/metabolismo , Camundongos , Viroses/metabolismo , Viroses/virologiaRESUMO
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.
Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Asma/imunologia , Células Dendríticas/imunologia , Imunidade Celular , Pyroglyphidae/imunologia , Células Th2/imunologia , Administração por Inalação , Transferência Adotiva , Alérgenos/isolamento & purificação , Animais , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/isolamento & purificação , Antígenos Ly/genética , Antígenos Ly/imunologia , Asma/patologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Movimento Celular , Proliferação de Células , Células Dendríticas/transplante , Expressão Gênica , Inflamação/imunologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/transplante , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Especificidade de Órgãos , Receptores de IgG/genética , Receptores de IgG/imunologiaRESUMO
The lymph nodes (LNs) and spleen have an optimal structure that allows the interaction between T cells, B cells and antigen-presenting dendritic cells (DCs) on a matrix made up by stromal cells. Such a highly organized structure can also be formed in tertiary lymphoid organs (TLOs) at sites of infection or chronic immune stimulation. This review focuses on the molecular mechanisms of TLO formation and maintenance, the controversies surrounding the nature of the inducing events, and the functions of these structures in infection, transplantation and autoimmunity.