Peroxisome proliferator-activated receptor-gamma in CD11c+ lung dendritic cells programs peripheral CD4+ T cells for Foxp3 induction during airway tolerance. (P6001)

Abstract

Abstract Peroxisome proliferator-activated receptor-gamma (PPARγ) is a widely expressed molecular regulator with anti-inflammatory functions. However, whether it has an anti-inflammatory role in dendritic cells (DCs) that influence the Treg/Teffector balance has not been experimentally addressed. In this study, we investigated the role of PPARγ in DCs regulating the delicate balance between tolerance versus inflammation in the periphery using a model of airway induced tolerance by inhaled allergen. Using mice with selective deletion of PPARγ in CD11c+ cells, we observed that PPARγ expression in CD11chi lung DCs is essential for de novo Foxp3 expression in CD4+ T cells. We demonstrate that PPARγ plays a crucial role in enhancing aldh1a2 expression in lung CD103+ DCs under tolerogenic conditions with significantly less expression of the enzyme in these cells when mice are immunized for airway inflammation. When tolerized CD11ccre/+ PPARγfl/fl mice were antigen-challenged, a complete loss of immune tolerance with increased neutrophil-dominated airway inflammation was observed. Taken together, our study identifies PPARγ as a central regulator in DC-mediated programming of Foxp3 expression in naive CD4+ T cells dictating tolerance versus inflammation upon antigen provocation.