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Flt3-L Increases CD4⁺CD25⁺Foxp3⁺ICOS⁺ Cells in the Lungs of Cockroach-Sensitized and -Challenged Mice

Departments of ¹ Biomedical Sciences, ² Medical Microbiology & Immunology, and ³ Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska

Correspondence and requests for reprints should be addressed to Devendra K. Agrawal, Ph.D., M.B.A., Departments of Biomedical Sciences, Internal Medicine, and Medical Microbiology & Immunology, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178. E-mail: dkagr{at}creighton.edu

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^highCD8^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; 250 µg) and Flt3-L (3 µg) 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-, 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- 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 could be a therapeutic strategy for the management and prevention of allergic asthma.

Key Words: airway hyperresponsiveness • anti-CD25 antibody • Fms-like tyrosine kinase 3 ligand • Forkhead winged helix transcription factor box P3 • naturally occurring CD4⁺CD25⁺ T-regulatory cells

CLINICAL RELEVANCE Fms-like tyrosine kinase 3 ligand could prove to be a novel mediator in controlling clinically-relevant allergen-induced immune response by increasing the density of CD4+CD25+Foxp3+ICOS+IL-10+ T-regulatory cells in asthmatic lung.