== a – mDC defined as CD11c+, CD11b+, Gr1 b – pDC defined as CD11c+, CD11b, Gr1+ – indicates significant differences of p<0.05 between strains == Differences in allergen uptake are not due to differential URB754 DC subset recruitment == To determine if increased allergen uptake and activation of mDCs (A/J mice) or pDCs (C3H mice) observed following intratracheal sensitization resulted from a greater overall recruitment of the dominant DC subset to the lung, we examined the number of total mDCs and pDCs in the lungs of A/J and C3H mice at 24 and 72 hours after HDM sensitization. environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness. == Introduction == Allergic asthma, a disease that continues to rise in both incidence and morbidity in the developed world, manifests as recurrent episodes of wheezing, shortness of breath and coughing in response to environmental stimuli. Although the origins of asthma are complex, it is accepted that asthma results from an inappropriate, Th2-dominated immune response to environmental allergens in genetically predisposed individuals. In asthmatic individuals, allergen exposure facilitates expansion of pathogenic, allergen-specific Th2 cells producing IL-4, IL-5 and IL-13, cytokines which induce pulmonary eosinophilic inflammation, IgE synthesis, airway wall remodeling and airway hyperresponsiveness (AHR), hallmarks of allergic asthma[1]. In contrast, non-asthmatic individuals respond in a fundamentally different way, becoming tolerized through the activation of immunosuppressive CD4+CD25+ regulatory T cells secreting IL-10 and TGF[2],[3]. However, despite an increasingly sophisticated understanding of the pathogenesis of allergic asthma, the factors that promote the initial development of a pathogenic versus protective T cell response remain unknown. As professional antigen presenting cells, dendritic cells (DCs) are capable of skewing T cell differentiation towards a pathogenic or regulatory phenotype through a number of mechanisms. For example, the panel of co-stimulatory molecules expressed by DCs plays a role in the type of T cell response elicited - CD86 and OX40L contribute to the development of pathogenic Th2 cells,[4][6]while ICOS-L and PD-1/PD-L promote the development of protective regulatory T cells[7][11]. DCs also directly regulate T cell differentiation by producing cytokines that drive the differentiation/expansion of Th2 cells (IL-6 alone[12],[13]), Th17 cells (IL-6+TGF/IL-23[12],[14],[15]), Tregs (TGF/IL-10[16][18]) or Th1 cells (IL-12[19]). Identification of a DC-produced cytokine directly responsible for inducing the development of Th2 cells remains elusive, yet the Th2-skewing capacity of DCs can be influenced by a number of factors[20][25]. Finally, the recent identification of distinct DC subsets has provided another mechanism through which DCs may control the development of pathogenic or regulatory T cell responses. Myeloid DCs (mDCs), are effective T cell stimulators, inducing a variety of effector T cell responses (e.g. Th1, Th2 or Th17) dependent upon the types of stimuli they receive, and the compartment from which they are isolated[26][28]. In contrast, while plasmacytoid DCs URB754 (pDCs) strongly induce the development of regulatory T cells as a result of elevated PD-L1 expression[29][31], they can also induce the development of IFN-producing Th1 cells after viral exposure, or Th2 differentiation after exposure to IL-3[32],[33]. Thus, DCs can adapt to conditions present at the time of antigen encounter, promoting responses appropriate to the specific antigen, a response further fine-tuned by the types of DC subset involved in antigen presentation. Dendritic cells in the lung play an important role in the development of allergic airway responses. In the large airways, DCs form a network below the epithelial cell layer[34][36], a position from which they sample and transport inhaled antigens present in the airway lumen to lung-draining URB754 LNs, where T cell activation occurs[37]. Airway DCs increase in numbers following allergen challenge in both human, and animal models[38],[39]suggesting an important role for these cells in asthma. ARHGEF11 Indeed, transfer of Ag-pulsed, bone marrow-derived mDCs to the airways of nave animals is sufficient to sensitize mice for subsequent development of allergic asthma[40][43]. In contrast, adoptive transfer of Ag-pulsed, bone marrow-derived pDCs induces tolerance[29], elegantly.