Role of T cell TGF-β signaling in intestinal cytokine responses and helminthic immune modulation

Authors

  • M. Nedim Ince,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
    • Division of Gastroenterology (4544 JCP), University of Iowa Hospital and Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1009, USA Fax: +1-319-353-6399

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  • David E. Elliott,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
    2. Veterans Affairs Medical Center, Iowa City, IA, USA
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  • Tommy Setiawan,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tufts New England Medical Center, Boston, MA, USA
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  • Ahmed Metwali,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
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  • Arthur Blum,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tufts New England Medical Center, Boston, MA, USA
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  • Hung-lin Chen,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
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  • Joseph F. Urban,

    1. US Department of Agriculture, Agricultural Research Service, Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, Beltsville, MD, USA
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  • Richard A. Flavell,

    1. Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
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  • Joel V. Weinstock

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tufts New England Medical Center, Boston, MA, USA
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Abstract

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-β, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-β release. As TGF-β exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-β signaling in helminthic modulation of intestinal immunity. T cell TGF-β signaling is interrupted in TGF-β receptor II dominant negative (TGF-βRII DN) mice by T-cell-specific over-expression of a TGF-βRII DN. We studied LPMC responses in WT and TGF-βRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-β signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-β-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-βRII DN mice. Thus, T cell TGF-β signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-γ generation and H. polygyrus-mediated suppression of chronic colitis.

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