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Allergic Inflammatory Response to Short Ragweed Allergenic Extract in HLA-DQ Transgenic Mice Lacking CD4 Gene¹

Svetlana P. Chapoval^*, Koji Iijima, Eric V. Marietta^*, Michele K. Smart^*, Andrei I. Chapoval^*, Amy G. Andrews and Chella S. David^2,*

^* Department of Immunology, Allergic Diseases Research Laboratory, and Section of Veterinary Medicine, Mayo Clinic, Rochester, MN 55905

To investigate the role of HLA-DQ molecules and/or CD4⁺ T cells in the pathogenesis of allergic asthma, we generated HLA-DQ6 and HLA-DQ8 transgenic mice lacking endogenous class II (A^null) and CD4 genes and challenged them intranasally with short ragweed allergenic extract (SRW). We found that DQ6/CD4^null mice developed a strong eosinophilic infiltration into the bronchoalveolar lavage and lung tissue, while DQ8/CD4^null mice were normal. However, neither cytokines nor eosinophil peroxidase in the bronchoalveolar lavage of DQ6/CD4^null mice was found. In addition, the airway reactivity to methacholine was elevated moderately in DQ6/CD4^null mice compared with the high response in DQ/CD4⁺ counterparts and was only partially augmented by CD4⁺ T cell transfer. The DQ6/CD4^null mice showed Th1/Th2-type cytokines and SRW-specific Abs in the immune sera in contrast to a direct Th2 response observed in DQ6/CD4⁺ mice. The proliferative response of spleen mononuclear cells and peribronchial lymph node cells demonstrated that the response to SRW in DQ6/CD4^null mice was mediated by HLA-DQ-restricted CD4^-CD8^-NK1.1^- T cells. FACS analysis of PBMC and spleen mononuclear cells demonstrated an expansion of double-negative (DN) CD4^-CD8^-TCR⁺ T cells in SRW-treated DQ6/CD4^null mice. These cells produced IL-4, IL-5, IL-13, and IFN- when stimulated with immobilized anti-CD3. IL-5 ELISPOT assay revealed that DN T cells were the cellular origin of IL-5 in allergen-challenged DQ6/CD4^null mice. Our study shows a role for HLA-DQ-restricted CD4⁺ and DN T cells in the allergic response.

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