GM-CSF–Licensed CD11b+ Lung Dendritic Cells Orchestrate Th2 Immunity to Blomia tropicalis

Abstract

The Blomia tropicalis dust mite is prevalent in tropical and subtropical regions of the world. Although it is a leading cause of asthma, little is known how it induces allergy. Using a novel murine asthma model induced by intranasal exposure to B. tropicalis, we observed that a single intranasal sensitization to B. tropicalis extract induces strong Th2 priming in the lung draining lymph node. Resident CD11b+ dendritic cells (DCs) preferentially transport Ag from the lung to the draining lymph node and are crucial for the initiation of Th2 CD4+ T cell responses. As a consequence, mice selectively deficient in CD11b+ DCs exhibited attenuated Th2 responses and more importantly did not develop any allergic inflammation. Conversely, mice deficient in CD103+ DCs and CCR2-dependent monocyte-derived DCs exhibited similar allergic inflammation compared with their wild-type counterparts. We also show that CD11b+ DCs constitutively express higher levels of GM-CSF receptor compared with CD103+ DCs and are thus selectively licensed by lung epithelial-derived GM-CSF to induce Th2 immunity. Taken together, our study identifies GM-CSF–licensed CD11b+ lung DCs as a key component for induction of Th2 responses and represents a potential target for therapeutic intervention in allergy.

Hyperoxic Exposure of Immature Mice Increases the Inflammatory Response to Subsequent Rhinovirus Infection: Association with Danger Signals

“…Mouse lung DCs contain two major subpopulations: CD103+ CD11b low (or CD11b-negative) DCs and CD103-negative CD11b high DCs (41–43). CD103+ DCs produce IL-12 and IFN-γ (44–46) and predominantly elicit Th1 and Th17 responses (47), whereas CD11b high DCs primarily provoke a Th2 response (47, 48). We found that hyperoxic exposure was associated with an increase in lung CD103+, MHCII hi , CD86 hi DCs, a population of cells which was further increased upon viral infection.…”

Lung CD103+ dendritic cells restrain allergic airway inflammation through IL-12 production

“…In recent years, intense research interest has focused on the division of labor among the different pulmonary DC populations and how each contributes to the initiation and maintenance of Th2 immunity and allergen tolerance (9)(10)(11). The role of lung CD103 + cDC1s in this context is still debated and poorly understood, with reports suggesting opposing functions (10,(15)(16)(17).…”

“…Plasmacytoid DCs play a key role in the induction of Tregs that control exacerbated airway inflammation (9). CD11b + cDC2s mediate Th2 priming in response to house dust mite (HDM) and to Blomia tropicalis mites (10)(11)(12), leading to eosinophilic airway inflammation, mucus production, and AHR. CD11b + cDC2s also promote a Th17 response upon lung fungal infection with Aspergillus fumigatus (13).…”

Aligning bona fide dendritic cell populations across species

“…For example, murine lung CD11b + cDC2 are the primary drivers of Th2 responses following exposure to house dust mite allergens [82,95], and of Th17 immunity, through release of IL-23, both in the steady state and during Aspergillus fumigatus infection [40]. A subset of mouse CD11b + cDC2 also expresses CD103; these cells, which are unique to the intestine, produce the Th17-inducing cytokines IL-6 and IL-23 in steady state or following Citrobacter rodentium infection or following immunization with a TLR5 ligand [40,42,96], and also migrate to LNs where they induce Th1/17 (IL-17 + IFNc + ) CD4 + T cells.…”