Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Abstract

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung 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.

Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung

“…In the current study, both mDCs and pDCs were detected in the lungs of normal neonatal mice, although mDCs were typically more abundant than pDCs. We previously demonstrated that the numbers of mDCs present typically exceed pDCs by 10-25-fold in the adult mouse lung (58). Thus, in neonatal mice, the lung appears to be a more tolerogenic environment, capable of promoting the development of T regulatory rather than activated T effector cells.…”

Pneumococcal Components Induce Regulatory T Cells That Attenuate the Development of Allergic Airways Disease by Deviating and Suppressing the Immune Response to Allergen

“…4G). Once recruited, CCR7 + cells migrate out of the lung and into the lymph nodes (19,20). At the same time, there was an increase in Treg-promoting factors (IL-2 and TGF-b).…”

“…T+P-induced Tregs and suppression of AAD were associated with reductions in the number of DCs containing OVA in the MLNs and lung. This may be because T+P-induced Tregs induce Fas-Fas ligandmediated or perforin-dependent killing of DCs in the lung, leading to reduced numbers of DCs carrying OVA in the MLNs (20,41). Therapeutic inhibition of DCs in AAD has been reported previously and proposed as a potential treatment for asthma (43).…”

“…+ CD11b + mDCs play an important role in promoting Th2 responses in AAD (20). mDC activity is enhanced by the expression of costimulatory (CD80 and CD86) and activation (MHCII) molecules.…”

Snapshots of CD4+ T cell plasticity in the pathogenesis of allergic asthma

“…Environmental allergens such as house dust mite (HDM) causes lung eosinophilia (2). Followed by activation of lung epithelial cells and subsequent release of alarmins such as thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 (3,4), dendritic cells (DCs) and B cells participate to prime naïve CD4 T cells to differentiate them into Th2 effector cells to secrete Th2 cytokines (IL-4, IL-5 and IL-13) and to produce B cell-mediated humoral immune responses by Ig (immunoglobulin)-E (5,6). Recently platelets were shown to participate in HDM-induced asthma stimulating Th2 cell differentiation (7).…”