A neutrophil/TGF-β axis limits the pathogenicity of allergen-specific CD4+ T cells.

Gregory S. Whitehead,Derek J. Royer,Donald N. Cook,Keiko Nakano,Hideki Nakano,Catherine G. Burke,Seddon Y. Thomas

doi:10.1172/jci.insight.150251

Abstract

The intensity and longevity of inflammatory responses to inhaled allergens is determined largely by the balance between effector and regulatory immune responses, but the mechanisms that determine the relative magnitudes of these opposing forces remain poorly understood. We have found that the type of adjuvant used during allergic sensitization has a profound effect on both the nature and longevity of the pulmonary inflammation triggered by subsequent reexposure to that same provoking allergen. TLR ligand adjuvants and house dust extracts primed immune responses characterized by a mixed neutrophilic and eosinophilic inflammation that was suppressed by multiple daily allergen challenges. During TLR ligand–mediated allergic sensitization, mice displayed transient airway neutrophilia, which triggered the release of TGF-β into the airway. This neutrophil-dependent production of TGF-β during sensitization had a delayed, suppressive effect on eosinophilic responses to subsequent allergen challenge. Neutrophil depletion during sensitization did not affect numbers of Foxp3+ Tregs but increased proportions of Gata3+CD4+ T cells, which, upon their transfer to recipient mice, triggered stronger eosinophilic inflammation. Thus, a neutrophil/TGF-β axis acts during TLR-mediated allergic sensitization to fine-tune the phenotype of developing allergen-specific CD4+ T cells and limit their pathogenicity, suggesting a novel immunotherapeutic approach to control eosinophilia in asthma.

Highlights

Allergic asthma is a widespread, chronic inflammatory disease of the airways characterized by reversible airway obstruction, airway hyperresponsiveness (AHR), and inflammation [1]
Previous studies have shown that mice sensitized to an allergen using protease adjuvants develop a predominantly eosinophilic inflammation of the airway upon subsequent allergen challenge, whereas mice sensitized using the TLR ligands, LPS or flagellin, develop a mixed eosinophilic and neutrophilic inflammation after a single challenge [7]
Recent findings suggest that neutrophils that are recruited to the airways during allergic sensitization may drive regulatory activities that function to suppress disease progression

Summary

Introduction

Allergic asthma is a widespread, chronic inflammatory disease of the airways characterized by reversible airway obstruction, airway hyperresponsiveness (AHR), and inflammation [1]. Many types of environmental exposures have been associated with an increased incidence of asthma, but in most cases, the mechanistic links between these exposures and asthma pathogenesis are poorly understood. This is in part because asthma is not a single disease, but rather a spectrum of disease pathologies that can be distinguished by multiple parameters that include the nature of airway inflammation. Many patients display eosinophilic inflammation associated with type 2 immune responses, but almost half of patients display a noneosinophilic form of asthma, often with predominant neutrophilia [3, 4]. A better understanding of how specific pathways give rise to distinct asthma endotypes should in turn lead to novel targets and more precise strategies for therapeutic intervention

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Conclusion