Requirements for allergen-induced airway inflammation and hyperreactivity in CD4-deficient and CD4-sufficient HLA-DQ transgenic mice

Background: Airway inflammation is central to the pathogenesis of allergic asthma, and molecules that mediate this process obviously represent targets for therapy. Objective: To study the role of CD4⁺ T cells and/or HLA-DQ molecules in allergic asthma, we have generated and characterized models of short ragweed allergen (SRW)-induced inflammation using transgenic mice with HLA-DQ (DQ6 or DQ8), human CD4 (hCD4), or both on a genetic background that lacks mouse MHC II and CD4 (Aβ⁰/mCD4⁰). Methods: Mice were actively sensitized and later challenged intranasally with SRW allergenic extract. Bronchoalveolar lavage fluid composition, airway inflammation and hyperresponsiveness, blood eosinophil levels, and cell proliferation were examined. Results: In response to SRW treatment, both DQ6 and DQ8 transgenic mice expressing hCD4 developed pulmonary eosinophilia and associated lung tissue damage with increase in eosinophil peroxidase and T_H2 cytokines in bronchoalveolar lavage fluid, strong airway hyperreactivity, and persistent blood eosinophilia. The response was independent of mast cells/histamine pathway and was mediated by DQ-restricted hCD4⁺ T cells. Interestingly, lungs of CD4-deficient DQ6 transgenic mice showed an eosinophilic inflammation without local increase in cytokines and eosinophil peroxidase. The allergic reaction was absent in double-knockout mice and mice expressing either DQ8 or hCD4 alone. Conclusions: DQ6 molecules are critical to SRW-induced allergy and can operate in the presence or absence of CD4. However, both DQ antigens and CD4 molecules are critical for full manifestation of allergen-induced asthma in transgenic mice.