International Immunology Advance Access originally published online on August 28, 2006
International Immunology 2006 18(10):1421-1431; doi:10.1093/intimm/dxl075
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IL-4R signaling is required to induce IL-10 for the establishment of Th2 dominance
1 Institute of Immunology and Infection Research, Ashworth Laboratories, West Mains Road, University of Edinburgh, EH9 3JT, UK
2 Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Health Science Faculty, Cape Town, South Africa
Correspondence to: R. M. Maizels; E-mail: rick.maizels{at}ed.ac.uk
The requirement for IL-4 to promote differentiation of naive CD4+ T cells into Th2 effector cell populations was established by classical in vitro studies. More recent in vivo data, however, indicate that signaling through the IL-4R is not essential for acquisition of the Th2 phenotype. In order to reconcile these seemingly contradictory conclusions, we have taken advantage of the ability of the excretory/secretory antigens of the gastrointestinal nematode Nippostrongylus brasiliensis to down-regulate Th1 cell development and drive Th2 cell expansion. We show that the initial development of IL-4-producing T cells is independent of IL-4R signaling but that the subsequent expansion of IL-4-producing CD4+ T cells in a competitive environment that also contains Th1 potential is positively influenced by IL-4R signaling. We find that the production of IL-10 is the key IL-4R-dependent factor required to maintain Th2 dominance and that in the absence of IL-4R signaling, Th2 expansion can only be achieved by neutralization of Th1 cytokines. Moreover, in the absence of IL-4R signaling, reduced IL-10 production is due to the lack in expansion of an IL-10+ Th2 population, rather than a global defect in the production of IL-10 by CD4+ T cells. Thus, the evolution of Th2 dominance is achieved at the expense of Th1 cell development, normally restrained by IL-10 in an IL-4R-dependent manner. We conclude that Th2 cell development in response to N. brasiliensis antigen requires both IL-4 and IL-10 to act in concert on incipient populations of both Th1 and Th2 types.
Keywords: helminth, IL-4, IL-10, nematode, type 2 response
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