The IL-3/IL-5/GM-CSF common receptor plays a pivotal role in the regulation of Th2 immunity and allergic airway inflammation.
The eosinophil is a central effector cell in allergic asthma. Differentiation and function of eosinophils are regulated by the CD4 Th2 cytokines IL-3, IL-5, and GM-CSF, which all signal through a common beta receptor subunit (betac). Recent therapeutic approaches targeting IL-5 alone have not ablated tissue accumulation of eosinophils and have had limited effects on disease progression, suggesting important roles for IL-3 and GM-CSF. By using a mouse model of allergic airways inflammation, we show that allergen-induced expansion and accumulation of eosinophils in the lung are abolished in betac-deficient (betac-/-) mice. Moreover, betac deficiency resulted in inhibition of hallmark features of asthma, including airways hypersensitivity, mucus hypersecretion, and production of Ag-specific IgE. Surprisingly, we also identified a critical role for this receptor in regulating type 2 immunity. Th2 cells in the lung of allergen-challenged betac-/- mice were limited in their ability to proliferate, produce cytokines, and migrate to effector sites, which was attributed to reduced numbers of myeloid dendritic cells in the lung compartment. Thus, the betac plays a critical role in allergen-induced eosinophil expansion and infiltration and is pivotal in regulating molecules that promote both early and late phases of allergic inflammation, representing a novel target for therapy.
Asquith
Kelly L
KL
Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, Australia.
Ramshaw
Hayley S
HS
Hansbro
Philip M
PM
Beagley
Kenneth W
KW
Lopez
Angel F
AF
Foster
Paul S
PS
D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*
D000485:Allergens; D053648:Cytokine Receptor Common beta Subunit; D016207:Cytokines; D007377:Interleukin-3; D015848:Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor