title: Flt3-L increases CD4+CD25+Foxp3+ICOS+ cells in the lungs of cockroach-sensitized and -challenged mice.
abstract: 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(high)CD8 alpha(high)CD11b(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 microg) and Flt3-L (3 microg) 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-gamma, 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-gamma 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.
authors.affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Halvor S
authors.initials: HS
authors.lastname: McGee
authors.forename: Jehad H
authors.initials: JH
authors.lastname: Edwan
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology; D015704:CD4 Antigens / Q000378:metabolism*; D002452:Cell Count; D002469:Cell Separation; D003058:Cockroaches / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D060889:Inducible T-Cell Co-Stimulator Protein; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D012333:RNA, Messenger; C084881:flt3 ligand protein; D016210:Methacholine Chloride; D019041:L-Selectin