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Granulocyte Macrophage Colony–Stimulating Factor–Driven Respiratory Mucosal Sensitization Induces Th2 Differentiation and Function Independently of Interleukin-4

Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, Division of Respiratory Diseases and Allergy, McMaster University, Hamilton, Ontario, Canada; Millennium Pharmaceuticals Incorporated, Cambridge, Massachusetts; and MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Address correspondence to: Manel Jordana, M.D., Ph.D., HSC-4H21, McMaster University, 1200 Main Street West, Hamilton, ON, L8S 3Z5 Canada. E-mail: jordanam@mcmasterca

The development of T helper (Th)2 responses is a key step in the pathogenesis of asthma. Interleukin (IL)-4 is thought to be important, although not strictly necessary, for Th2 differentiation, although triggers of IL-4–independent Th2 polarization have not been identified. We examined whether IL-4 is necessary for Th2-polarized responses during granulocyte macrophage colony–stimulating factor (GM-CSF)–driven respiratory mucosal sensitization. Balb/c wild type (WT) or IL-4 knockout (4KO) mice were exposed to aerosolized ovalbumin (OVA) in the context of airway GM-CSF expression. We examined the extent of Th2 polarization using real-time quantitative polymerase chain reaction on lymph node mRNA, flow cytometric analysis of lung Th cells, and measurement of cells, cytokines, and immunoglobulins in bronchoalveolar lavage (BAL) and serum. GATA-3 and CCR3, -4, and -8 were expressed in the lymph nodes of WT and 4KO mice at similar levels, as were IL-5 and IL-13 levels in the BAL, T1/ST2 on lung Th cells, and BAL eosinophils after recall challenge. With the exception of immunoglobulin production, expression of GATA-3, CCR-3, -4, -8, IL-5, and T1/ST2, and the generation of blood eosinophilia, were intact in mice doubly deficient in both IL-4 and IL-13. We conclude that IL-4 is not required for the generation of Th2-polarized responses in the presence of GM-CSF.

Abbreviations: analysis of variance, ANOVA • bronchoalveolar lavage, BAL • double knockout, DKO • IL-4 knockout, 4KO • interferon, IFN • interleukin, IL • granulocyte macrophage colony–stimulating factor, GM-CSF • monocyte chemotactic protein, MCP • ovalbumin, OVA • phosphate-buffered saline, PBS • polymerase chain reaction, PCR • room temperature, rt • wild-type, WT

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