Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation.

:The aim of this study was to investigate whether dendritic cells (DCs) can induce sensitization to aeroallergen in a mouse model of allergic asthma. Ovalbumin-pulsed (OVA-pulsed) or unpulsed myeloid DCs that were injected into the airways of naive mice migrated into the mediastinal lymph nodes. When challenged 2 weeks later with an aerosol of OVA, activated CD4 and CD8 lymphocytes, eosinophils, and neutrophils were recruited to the lungs of actively immunized mice. These CD4(+) lymphocytes produced predominantly IL-4 and IL-5 but also IFN-gamma, whereas CD8(+) lymphocytes produced predominantly IFN-gamma. Histological analysis revealed perivascular and peribronchial eosinophilic infiltrates and goblet cell hyperplasia. Studies in IL-4(-/-) and CD28(-/-) mice revealed that production of IL-4 by host cells and provision of costimulation to T cells by DCs were critical for inducing the response. Lung CD4(+) T cells strongly expressed the Th2 marker T1/ST2, and signaling through this molecule via a ligand expressed on DCs was essential for the establishment of airway eosinophilia. These data demonstrate that DCs in the airways induce sensitization to inhaled antigen and that molecules expressed on the surface of these cells are critical for the development of Th2-dependent airway eosinophilia.

Lambrecht BN ，De Veerman M ，Coyle AJ ，Gutierrez-Ramos JC ，Thielemans K ，Pauwels RA ... -  《JOURNAL OF CLINICAL INVESTIGATION》

Differential capacity of CD8+ alpha or CD8- alpha dendritic cell subsets to prime for eosinophilic airway inflammation in the T-helper type 2-prone milieu of the lung.

Hammad H ，de Vries VC ，Maldonado-Lopez R ，Moser M ，Maliszewski C ，Hoogsteden HC ，Lambrecht BN ... -  《CLINICAL AND EXPERIMENTAL ALLERGY》

Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization.

Kuipers H ，Heirman C ，Hijdra D ，Muskens F ，Willart M ，van Meirvenne S ，Thielemans K ，Hoogsteden HC ，Lambrecht BN ... -  《JOURNAL OF LEUKOCYTE BIOLOGY》

Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice.

Lambrecht BN ，Salomon B ，Klatzmann D ，Pauwels RA ... -  《JOURNAL OF IMMUNOLOGY》

Essential role of dendritic cell CD80/CD86 costimulation in the induction, but not reactivation, of TH2 effector responses in a mouse model of asthma.

Airway dendritic cells (DCs) are crucial for the generation of TH2 cells from naive T cells during sensitization and for reactivation of primed TH2 cells on allergen challenge in mouse models of asthma. It is unknown whether CD80/CD86 costimulation is necessary during both phases of the response because primed T cells rely less on costimulatory molecules compared with naive T cells. We sought to study the contribution of CD80/CD86 costimulatory molecules on DCs during sensitization or challenge in a mouse model of asthma. Naive BALB/c mice received an intratracheal injection of ovalbumin (OVA)-pulsed DCs obtained from the bone marrow of wild-type (WT) or CD80/CD86-/- mice and were subsequently challenged with OVA aerosol to address the role of costimulation during sensitization. OVA-sensitized mice received OVA-pulsed WT or CD80/CD86-/- DCs without OVA aerosol to address the role of costimulation during challenge. WT DCs induced the proliferation and effector TH2 differentiation of naive OVA-specific T cells, whereas CD80/CD86-/- DCs induced only proliferation. Not surprisingly, WT DCs but not CD80/CD86-/- DCs induced sensitization to OVA in naive mice. In contrast, in OVA-sensitized mice intratracheal injection of CD80/CD86-/- OVA-pulsed DCs led to eosinophilic airway inflammation, goblet cell hyperplasia, and effector TH2 cytokine production that was not different from that seen after injection with WT OVA-DCs, even when the inducible costimulator ICOS was blocked or cytotoxic T lymphocyte-associated antigen 4 immunoglobulin was given. CD80/CD86 costimulation on DCs is only necessary during priming of naive T cells into TH2 cells but not during restimulation of previously primed TH2 cells in the challenge phase.

van Rijt LS ，Vos N ，Willart M ，Kleinjan A ，Coyle AJ ，Hoogsteden HC ，Lambrecht BN ... -  《JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY》