Attenuation of allergen-induced responses in CCR6-/- mice is dependent upon altered pulmonary T lymphocyte activation.
We have established a defect in CCR6-/- mice in response to a cockroach allergen airway challenge characterized by decreased IL-5 production, reduced CD4+ T and B cells as well as decreased eosinophil accumulation. To determine the nature of the defect in CCR6-/- mice T lymphocyte populations from allergen-sensitized wild-type mice were transferred into sensitized CCR6-/- mice. The reconstituted response was characterized by an increase in IL-5 levels, eosinophil accumulation, and serum IgE levels in recipient CCR6-/- mice. Analysis of lymphocytes from draining lymph nodes of CCR6+/+ and CCR6-/- sensitized or challenged mice demonstrated a significant decrease in IL-5 and IL-13 production in CCR6-/- mice. In contrast, the systemic response in allergen-rechallenged spleen cells demonstrated no significant alteration in allergen-induced cytokine production. Transfer of isolated splenic T lymphocytes from sensitized CCR6+/+ mice induced airway hyperresponsiveness in wild-type but not CCR6-/- naive mice, suggesting that T cells alone were not sufficient to induce airway hyperresponsiveness in CCR6-/- mice. Additional analysis demonstrated decreased CD11c+, CD11b+ and CD11c, and B220 subsets of dendritic cells in the lungs of CCR6-/- mice after allergen challenge. Using in vitro cell mixing studies with isolated pulmonary CD4+ T cells and CD11c+ cells from CCR6+/+ or CCR6-/- mice, we demonstrate alterations in both CCR6-/- T cells and CCR6-/- pulmonary APCs to elicit IL-5 responses. Altogether, the defect in CCR6-/- mice appears to be primarily due to an alteration in T cell activation, but also appears to include local pulmonary APC defects.
Lundy
Steven K
SK
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Lira
Sergio A
SA
Smit
Jetse J
JJ
Cook
Donald N
DN
Berlin
Aaron A
AA
Lukacs
Nicholas W
NW
D019264:Adoptive Transfer; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000637:transplantation; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003058:Cockroaches / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation
D000485:Allergens; C106311:CCR6 protein, human; C498126:CCR6 protein, mouse; D016207:Cytokines; D054399:Receptors, CCR6; D019707:Receptors, Chemokine