Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation

Abstract

Recent studies highlight the role of Treg in preventing unnecessary responses to allergens and maintaining functional immune tolerance in the lung. We investigated the role of Treg during the sensitization phase in a murine model of experimental allergic airway inflammation by selectively depleting the Treg population in vivo. DEpletion of REGulatory T cells (DEREG) mice were depleted of Treg by diphtheria toxin injection. Allergic airway inflammation was induced using OVA as a model allergen. Pathology was assessed by scoring for differential cellular infiltration in bronchoalveolar lavage, IgE and IgG1 levels in serum, cytokine secretion analysis of lymphocytes from lung draining lymph nodes and lung histology. Use of DEREG mice allowed us for the first time to track and specifically deplete both CD25 1 and CD25 À Foxp31 Treg, and to analyze their significance in limiting pathology in allergic airway inflammation. We observed that depletion of Treg during the priming phase of an active immune response led to a dramatic exacerbation of allergic airway inflammation in mice, suggesting an essential role played by Treg in regulating immune responses against allergens as early as the sensitization phase via maintenance of functional tolerance. Key words: Allergic airway inflammation . Depletion of regulatory T cells (DEREG). IntroductionThere has been a dramatic increase in prevalence of allergic disorders such as allergic rhinitis (hay fever), atopic dermatitis (eczema) and asthma in the past few decades, especially in developed countries [1,2]. Given that allergic airway inflammation has been associated with dysregulated Th2 immune response [3], the increased prevalence of allergy has been explained by the revised hygiene hypothesis [4,5]. This hypothesis suggests that early childhood infections prime immune-regulation and mediate protection from allergies by driving development of regulatory mechanisms rather than provoking aggressive immune responses [6,7]. This definition, in an extension of the original hygiene hypothesis proposing a Th1- . However, a similar approach also employing CD25 1 T-cell depletion produced conflicting results, demonstrating reduced Th2 cytokine production and no effect on eosinophilic inflammation [16]. Conversely, another study shows that mice pretransplanted with CD4 + CD25 + T-celldepleted splenocytes exhibited decreased antigen-induced eosinophil recruitment into the airways and reduced Th2 differentiation and cytokine production which were restored on supplementation with CD25 1 T cell fraction [17]. Finally, mouse strain-specific differences have been observed in the course of CD25 1 T-cell depletion, where depletion of Treg in an allergy resistant strain of mice C3H led to massive exacerbation of airway inflammation, while Treg depletion in the allergic sensitive mice strain A/J showed only mild differences [14]. Although most of the work has been focused on CD25 ResultsTreg depletion leads to enhanced eosinophil infiltration in BAL fluid in an inflammation modelTo examine ...

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