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Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma

Joerg Mattes¹, Ming Yang¹, Surendran Mahalingam¹, Joachim Kuehr², Dianne C. Webb¹, Ljubov Simson¹, Simon P. Hogan¹, Aulikki Koskinen¹, Andrew N.J. McKenzie⁵, Lindsay A. Dent³, Marc E. Rothenberg⁴, Klaus I. Matthaei¹, Ian G. Young¹ and Paul S. Foster¹

¹ Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, 0200, Australia
² University Children's Hospital of Freiburg, D-79106 Freiburg, Germany
³ Department of Molecular Biosciences, University of Adelaide, South Australia 5005, Australia
⁴ Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH 45229
⁵ Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom

Address correspondence to Paul S. Foster, Allergy and Inflammation Group, Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, 0200, Australia. Phone: 61-261252032; Fax: 61-261250415; E-mail: Paul.Foster{at}anu.edu.au

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti–IL-5 or anti–IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin^-/-) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4⁺ T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin^-/- mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.

Key Words: allergy • cytokines • eosinophils • lung • inflammation

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