Interleukin-4 is required for the induction of lung Th2 mucosal immunity.
Aerosol antigen challenge of ovalbumin-sensitized mice induced an eosinophilic airway inflammation that was dependent on interleukin (IL)-5 and CD4+, but not CD8+, T lymphocytes. The involvement of the Th2 phenotype of CD4+ T cells was supported by demonstrating that FACS-sorted purified lung T cells from sensitized, but not control, mice produced IL-4, IL-5, and IL-10 after activation of the CD3/TCR complex. To determine the role of IL-4 in this process, we used mice in which the gene for IL-4 was deleted by homologous recombination. Antigen challenge of IL-4 gene-targeted mice resulted in a marked attenuation of eosinophilic inflammation and IL-5 secretion. To more fully understand the time when IL-4 was involved, we administered a neutralizing anti-IL-4 antibody (11B11) either immediately before antigen challenge or during immunization. Inhibition of IL-4 before antigen challenge had little effect on antigen-induced eosinophil infiltration. However, when 11B11 was administered during immunization, there was a marked reduction in eosinophil infiltration. Cross-linking of the CD3/TCR complex of FACS-sorted lung T cells revealed that only when anti-IL-4 was administered during immunization was there an inhibition of T cell-derived IL-5 and IgE production. These results suggest that IL-4 is central both to the induction of a local Th2 response and to the development of eosinophilic inflammation of the lung. Moreover, we suggest a sequential involvement of IL-4 and IL-5, with IL-4 committing naive T cells to a Th2 phenotype which upon activation by aerosol provocation secrete IL-5, resulting in eosinophil accumulation.
Coyle
A J
AJ
Department of Asthma and Allergy, Ciba-Geigy Ltd., Basel, Switzerland.
Le Gros
G
G
Bertrand
C
C
Tsuyuki
S
S
Heusser
C H
CH
Kopf
M
M
Anderson
G P
GP
D000818:Animals; D002469:Cell Separation; D004804:Eosinophils / Q000276:immunology; D005434:Flow Cytometry; D017353:Gene Deletion; D007111:Immunity, Cellular / Q000276:immunology*; D007249:Inflammation / Q000209:etiology / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology*
D015847:Interleukin-4; D010047:Ovalbumin