Identification and characterization of IL-4-producing cells in the sensitization and effector phases of asthma development.

摘要

Asthma is a chronic pulmonary disease involving a sensitization and an effector phase. The sensitization phase of asthma begins with allergen recognition by naive CD4+ T cells in secondary lymphoid organs. After allergen exposure, naïve T cells become activated and can differentiate into Th2 effector cells in the presence of yet undefined “initial” IL-4. The effector phase occurs after sensitized individuals are exposed to inhaled allergen and is characterized by an increased serum immunoglobulin (Ig) E, mucus overproduction in the lumen of airways, infiltration of eosinophils, and hypertrophy of goblet cells. Inflammation perpetuates with each exposure to inhaled allergen, leading to exacerbation of clinical symptoms, including wheezing, dyspnea, and sputum production.; How the Th2 response is initiated is not known particularly, what cell type produces “initial” IL-4. A unique model system examined IL-4 producers during asthma development. In this GFP C57BL/6 transgenic model, GFP replaced IL-4 on both alleles or on one allele. Following peripheral immunization with OVA + alum, the majority of IL-4-independent IL-4 producers from secondary lymphoid tissue expressed CD4. The majority of CD4+GFP+ cells were TCRVβ+, whereas one-sixth were NK T cells. These results suggest conventional TCRαβCD4+ T cells were the predominant IL-4-independent IL-4-producing cells in the sensitization phase.; In the effector phase, the predominant cellular source of IL-4 in the BAL and lung in response to OVA intranasal challenge were CD4− and only a small population was CD4+. The majority of CD4−GFP+ cells in BAL and lung were identified morphologically as eosinophils. GFP fluorescence intensity was greater in CD4−GFP+ cells than CD4+GFP+ cells from these compartments, suggesting eosinophils were the predominant and robust IL-4 producers in BAL and lung during the effector phase. The percentage of CD4+GFP+ cells significantly increased following OVA intranasal challenge when compared to PBS control mice. These cells were characterized as TCRVβ, suggesting a conventional TCRαβCD4+ T cell phenotype. In contrast to findings obtained from peripheral lymphoid organs, no NK T GFP+ cells were observed. This study provides an insight to the understanding of the sensitization and effector phases of asthma pathogenesis, which may be useful for therapeutic interventions.