Allergic inflammatory response to short ragweed allergenic extract in HLA-DQ transgenic mice lacking CD4 gene.
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 (Abeta(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(-)TCRalphabeta(+) T cells in SRW-treated DQ6/CD4(null) mice. These cells produced IL-4, IL-5, IL-13, and IFN-gamma 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.
Chapoval
Svetlana P
SP
Department of Immunology, Allergic Diseases Research Laboratory, and Section of Veterinary Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Iijima
Koji
K
Marietta
Eric V
EV
Smart
Michele K
MK
Chapoval
Andrei I
AI
Andrews
Amy G
AG
David
Chella S
CS
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000097:blood; D000918:Antibody Specificity / Q000235:genetics; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D000939:Epitopes / Q000097:blood; D017353:Gene Deletion; D006683:HLA-DQ Antigens / Q000235:genetics*; D006801:Humans; D007274:Injections, Intraperitoneal; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010936:Plant Extracts / Q000008:administration & dosage / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D000485:Allergens; D000906:Antibodies; D015704:CD4 Antigens; D016207:Cytokines; D000939:Epitopes; D006683:HLA-DQ Antigens; D010936:Plant Extracts