Flt3-L increases CD4+CD25+Foxp3+ICOS + cells in the lungs of cockroach-sensitized and -challenged mice

We previously reported in an ovalbumin-induced model of allergic asthma that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c^highCD8α^highCD11b^low dendritic cells in the lung. In this study, we investigated the effect of Flt3-L in a clinically relevant aeroallergen-induced asthma on the phenotypic expression of lung T cells. Balb/c mice were sensitized and challenged with cockroach antigen (CRA), and AHR to methacholine was established. These mice received three intraperitoneal injections of anti-CD25 antibody (PC61; 250μg) and Flt3-L (3μg) daily for 10 days. Cytokines and Ig levels in the serum were measured and differential bronchoalveolar lavage fluid (BALF) cell counts were examined. Flt3-L reversed AHR to methacholine to the control level. Flt3-L significantly decreased levels of BALF IL-5, IFN-γ, eosinophilia and substantially increased IL-10 and the number of CD4⁺CD25⁺ Forkhead winged helix transcription factor box P3 (Foxp3⁺) IL-10 ⁺ T cells in the lung. Administration of PC61 antibody blocked the effect of Flt3-L and substantially increased AHR, eosinophilia, and BALF IL-5 and IFN-γ levels, and decreased BALF IL-10 levels and the number of CD4⁺CD25⁺Foxp3⁺IL-10⁺ T cells. Flt3-L significantly decreased CD62-L, but increased inducible costimulatory molecule and Foxp3 mRNA expression in the CD4⁺CD25⁺ T cells isolated from lungs of Flt3-L-treated, CRA-sensitized mice compared to CRA-sensitized mice without Flt3-L treatment and PBS control group. Flt3-L significantly inhibited the effect of CRA sensitization and challenge to increase GATA3 expression in lung CD4⁺CD25⁺ T cells. Collectively, these data suggest that the therapeutic effect of Flt3-L is mediated by increased density of naturally occurring CD4⁺CD25 ⁺Foxp3⁺IL-10⁺ICOS⁺ T-regulatory cells in the lung. Flt3-L couldbe a therapeutic strategy for the management and prevention of allergic asthma.