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Infection and Immunity, December 2008, p. 5535-5542, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00210-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Interleukin-4-Promoted T Helper 2 Responses Enhance Nippostrongylus brasiliensis-Induced Pulmonary Pathology

Helen Mearns,^, William G. C. Horsnell, J. Claire Hoving, Benjamin Dewals, Antony J. Cutler, Frank Kirstein, Elmarie Myburgh,^¶ Berenice Arendse, and Frank Brombacher^*

International Centre for Genetic Engineering and Biotechnology and Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

Received 15 February 2008/ Returned for modification 7 April 2008/ Accepted 29 August 2008

The role of CD4⁺ T-cell interleukin-4 (IL-4) receptor alpha (IL-4R) expression in T helper 2 (TH2) immune responses has not been defined. To examine this role, we infected CD4⁺ T-cell IL-4R knockout (KO) mice with the parasitic nematode Nippostrongylus brasiliensis, which induces strong host TH2 responses. Although N. brasiliensis expulsion was not affected in CD4⁺ T-cell IL-4R KO mice, the associated lung pathology was reduced. Infected CD4⁺ T-cell IL-4R KO mice showed abrogation of airway mucus production. Furthermore, CD4⁺ T-cell IL-4R KO mouse lungs contained reduced numbers of lymphocytes and eosinophils. Restimulation of pulmonary region-associated T-cell populations showed that TH2 cytokine responses were disrupted. Secretion of IL-4, but not secretion of IL-13 or IL-5, from mediastinal lymph node CD4⁺ T cells was reduced in infected CD4⁺ T-cell IL-4R KO mice. Restimulation of tissue-derived CD4⁺ T cells resulted in equivalent levels of IL-4 and IL-13 on day 7 postinfection (p.i.) in control and CD4⁺ T-cell IL-4R KO mice. By day 10 p.i. the TH2 cytokine levels had significantly declined in CD4⁺ T-cell IL-4R KO mice. Restimulation with N. brasiliensis antigen of total lung cell populations and populations with CD4⁺ T cells depleted showed that CD4⁺ T cells were a key TH2 cytokine source. These data demonstrated that CD4⁺ T-cell IL-4 responsiveness facilitates eosinophil and lymphocyte recruitment, lymphocyte localization, and TH2 cytokine production in the allergic pathology associated with N. brasiliensis infections.

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* Corresponding author. Mailing address: International Centre for Genetic Engineering and Biotechnology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. Phone: 27214066424. Fax: 27214066029. E-mail: fbrombac{at}uctgsh1.uct.ac.za

Published ahead of print on 22 September 2008.

Editor: J. F. Urban, Jr.

H.M. and W.G.C.H. contributed equally to this study.

Present address: Malaghan Institute of Medical Research, Victoria University, Wellington, New Zealand.

Present address: Histocompatibility and Immunogenetics, NHSBT, Colindale Centre, London, United Kingdom.

^¶ Present address: Wellcome Centre for Molecular Parasitology and Division of Infection & Immunity, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.

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Infection and Immunity, December 2008, p. 5535-5542, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00210-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.