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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901341v1 183/11/7531    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Shao, Z. Articles by Agrawal, D. K. PubMed PubMed Citation Articles by Shao, Z. Articles by Agrawal, D. K.

Fms-Like Tyrosine Kinase 3 Ligand Regulates Migratory Pattern and Antigen Uptake of Lung Dendritic Cell Subsets in a Murine Model of Allergic Airway Inflammation¹

Zhifei Shao,^* Toluwalope O. Makinde,^* Halvor S. McGee,^* Xiang Wang,^* and Devendra K. Agrawal^2*

Departments of ^*Biomedical Sciences, Medical Microbiology and Immunology, and Internal Medicine, Creighton University of School of Medicine, Omaha, NE 68178

Fms-like tyrosine kinase 3 ligand (Flt3L) reverses the features of allergic airway inflammation and increases a Th2-suppressive regulatory lung CD11c^highCD11b^low dendritic cell (DC) subset in a mouse model. We examined the migratory pattern and Ag uptake efficiency of lung DC subsets in the therapeutic effect of Flt3L. Lung CD11c^highCD11b^low and CD11c^lowCD11b^high DCs from PBS-treated, OVA-sensitized, and Flt3L-treated/OVA-sensitized BALB/c mice were sorted using MACS and FACS for phenotype analysis. Lymphatic chemokine expression in thoracic lymph nodes was determined by immunohistochemistry. Migration of two lung DC subsets to lymphatic chemokines was examined in vitro using a Transwell chemotaxis assay. Labeled Ag was intranasally delivered into mouse lung to track the migration and Ag uptake of lung DCs. The in vitro cytokine secretion of mediastinal lymph node cells was determined using ELISA. CD11c^lowCD11b^high DCs have higher expression of CCR5, CCR6, and CCR7, but lower expression of CCR2 than CD11c^highCD11b^low DCs. CD11c^lowCD11b^high DCs in Flt3L-treated/OVA-sensitized mice demonstrated a less mature phenotype, inefficiency in Ag uptake, and impaired migration in vitro to lymphatic chemokine than those in OVA-sensitized mice. Administration of Flt3L decreased the expression of CCR5 and CCR7 in CD11c^lowCD11b^high DCs in OVA-sensitized mice. Fewer Ag-carrying cells were detected in the lungs and lymph nodes in Flt3L-treated/OVA-sensitized mice than OVA-sensitized mice with a greater decrease in CD11c^lowCD11b^high DCs. Mediastinal lymph node cells from Flt3L-treated mice secreted higher levels of Th1 cytokines and IL-10 than OVA-sensitized mice in vitro. In conclusion, Flt3L-generated lung immunogenic CD11c^lowCD11b^high DCs have a less mature phenotype, impaired Ag uptake, and impaired migration to draining lymph nodes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 HL070885 and R01 AI075315, and LB506 Nebraska Cancer and Smoking-Related Disease Program, Department of Health, Nebraska.

² Address correspondence and reprint requests to Dr. Devendra K. Agrawal, CRISS II Room 510, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178. E-mail address: dkagr{at}creighton.edu

³ Abbreviations used in this paper: Flt3, Fms-like tyrosine kinase 3; DC, dendritic cell; Flt3L, Flt3 ligand; LN, lymph node.