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

Ian P Lewkowich,Jennifer R Clark,Marsha Wills-Karp,Stephane Lajoie,Alyssa A Sproles,Nancy S Herman,Derya Unutmaz

doi:10.1371/journal.pone.0003879

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.

Highlights

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
We demonstrate that following allergen exposure in susceptible hosts, allergen uptake is predominantly by pulmonary myeloid DC (mDC) capable of high level co-stimulatory molecule expression and the production of Th17-promoting cytokines production (IL-6, IL-23), and that these factors are critical for the development of allergen-induced airway hyperresponsiveness
Differences in allergen uptake are not due to differential dendritic cells (DCs) subset recruitment To determine if increased allergen uptake and activation of mDCs (A/J mice) or plasmacytoid DCs (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 house dust mite (HDM) sensitization

Summary

Introduction

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. 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, [4,5,6] while ICOS-L and PD-1/PD-L promote the development of protective regulatory T cells [7,8,9,10,11]. 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 [20,21,22,23,24,25]. While plasmacytoid DCs (pDCs) strongly induce the development of regulatory T cells as a result of elevated PD-L1 expression [29,30,31], they can induce the development of IFNc-producing Th1 cells after viral exposure, or

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