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Regulatory T cells contribute to allergen tolerance induced by daily airway immunostimulant exposures.

ABSTRACT: Endotoxin and other immunostimulants ubiquitous in ambient air are potent mucosal adjuvants, yet only a minority of individuals develop aeroallergen hypersensitivities, whereas the majority develop tolerance. These investigations were performed to reconcile this paradox. During initial experiments, mice received a primary series of weekly intranasal OVA immunizations (1(0) vaccination). Selected mice also received intranasal sterile house dust extract (HDE) with each OVA vaccination, at a dose previously found to exert adjuvant activity. A third group of OVA-vaccinated mice received intranasal HDE on a daily basis, but at one seventh the adjuvant dose, beginning 1 week before the first and ending with the last 1(0) OVA vaccination. Mice were then left untreated for 4 weeks, and then received a secondary series of weekly intranasal OVA immunizations with adjuvant doses of HDE (2(0) sensitization). Three weeks later, OVA-specific airway challenges and immune responses were assessed. Analogous experiments were conducted with LPS. Mice receiving daily intranasal HDE or LPS during 1(0) OVA vaccination were highly resistant to 2(0) sensitization, whereas the mice in other experimental groups readily developed Th2-biased airway hypersensitivity. Tolerance was associated with poor OVA-specific CD4 cell proliferation and with local natural T-regulatory cell (Treg) expansion. Finally, Treg depletion by delivery of the anti-CD25 monoclonal antibody during 1(0) vaccination attenuated the tolerogenic effects of daily airway HDE exposures. These studies suggest that regular airway immunostimulant exposures selectively increase local Treg numbers and activity in an antigen-independent manner, thereby promoting the development of aeroallergen tolerance.

SUBMITTER: Lee SM

PROVIDER: S-EPMC3095935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAirway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis.ObjectiveWe tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine.MethodsAirway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA.ResultsWe made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-γ- and IL-10-producing regulatory CD4+CD25+ forkhead box p3 (Foxp3)+ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model.ConclusionWe report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.

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Regulatory T cells contribute to allergen tolerance induced by daily airway immunostimulant exposures.

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