Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism

Abstract

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

“…The technical difficulties in accurately measuring these cytokines in biological fluids (29,39) might have contributed to the low amounts detected. However, we recently showed that BALF of HDE-treated mice contains an activity that enhances the ability of DCs to direct Th2 differentiation in vitro, and that this activity is independent of IL-33, TSLP, and IL-25 (40). It is possible, therefore, that binding of TNF to its receptor on AECs releases an unidentified factor that contributes to the Th2-promoting activity of lung DCs.…”

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

“…Moreover, cDC2s were recently reported to induce Tfh cell responses against inhaled antigens, although this study was performed in the absence of Th2 adjuvants and therefore IgE responses could not be assessed . However, we and others have previously found that lung cDC1s from ID‐exposed mice are capable of stimulating Th2 cell differentiation . Furthermore, both gut and splenic cDC1s have been shown to prime antigen‐specific Tfh cells’ cell responses, raising the possibility that lung cDC1s may do the same under certain conditions.…”

“…Because children spend the vast majority of their lives indoors, it is likely that exposures within the home environment influence allergic disease development . Within the home, children are exposed to a variety of immunostimulatory molecules, including allergens and microbial products, which can act as adjuvants in the respiratory tract and promote allergic sensitization to inhaled antigens . While indoor environmental exposures are known to contribute to wheezing and asthma inception in children, there is increasing evidence that the home environment may also impact food allergy development .…”

“…In addition to food allergens, indoor dust contains a mixture of environmental agents with immunostimulatory properties, including endotoxin, fungal‐derived polysaccharides, and proteases . These environmental agents can act as adjuvants in the respiratory tract and promote allergic sensitization to normally innocuous antigens in animal models . It is likely that the composition of environmental adjuvants in indoor dust can significantly influence sensitization and allergy development.…”

“…Indeed, the bioactivity of indoor dust has been associated with aeroallergen sensitization in children at risk for allergy . We have previously shown that indoor dust extracts can programme lung cDCs to induce Th2 responses to inhaled antigens, resulting in the development of allergic airway inflammation upon subsequent inhalational allergen challenge . Whether adjuvants in indoor dust can also promote the development of allergy to environmental food allergens is unknown.…”