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IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice

Nature Immunology volume 2, pages 1054–1060 (2001)Cite this article

Abstract

Immunity to infection with intracellular pathogens is regulated by interleukin 12 (IL-12), which mediates protective T helper type 1 (TH1) responses, or IL-4, which induces TH2 cells and susceptibility. Paradoxically, we show here that when present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes.

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Figure 1: IL-4 instructs DCs to produce increased amounts of IL-12 and to promote TH1 development in vitro.
Figure 2: IL-4 instructs resistance to L. major in susceptible BALB/c mice.
Figure 3: IL-4 instructs parasite containment in susceptible BALB/c mice.
Figure 4: IL-4 treatment during the first 8 h of L. major infection instructs IL-12–producing DC1s and suppresses IL-4 expression.
Figure 5: Induction of TH1 responses with IL-4 depends on IL-12.
Figure 6: Treatment with anti–IL-12 abrogates IL-4–induced resistance to L. major in BALB/c mice.
Figure 7: Extension of IL-4 treatment into the period of T cell priming reverses IL-4–induced resistance to L. major.
Figure 8: Timing determines whether IL-4 treatment instructs a TH1 phenotype and resistance or a TH2 phenotype and susceptibility to L. major in TCR Vβ4-deficient mice.

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Acknowledgements

We thank W. E. Paul, E. M. Shevach (Laboratory of Immunology, NIAID, NIH), G. Riethmüller and T. Brocker (Department of Immunology, Munich) for helpful discussions and critically reading the manuscript and B. von Restorff for technical assistance. Supported by the Deutsche Forschungsgemeinschaft RO 764/8-1 and 676/1, SFB 217 and SFB 456, the Wilhelm Sander-Stiftung (97.041.2) and the Swiss National Science Fdt.

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Author notes

  1. Tilo Biedermann

    Present address: Novartis Research Institute, Brunnerstr. 59, A-1235, Vienna, Austria

  2. Pascal Launois

    Present address: Pasteur Institute, Cayenne, French Guyana

  3. Tilo Biedermann, Stephan Zimmermann, Hayo Himmelrich and Alain Gumy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology and Allergology, Ludwig-Maximilians-University Munich, Frauenlobstr. 9–11, Munich, 80337, Germany

    Tilo Biedermann, Oliver Egeter, Arne K. Sakrauski & Martin Röcken

  2. Department of Microbiology, Technical University Munich, Munich, Germany

    Stephan Zimmermann, Irene Seegmüller, Hermann Wagner & Klaus Heeg

  3. Department of Microbiology, University of Marburg, Marburg, Germany

    Stephan Zimmermann & Klaus Heeg

  4. WHO Immunology Research and Training Center, Institute of Biochemistry, University of Lausanne, Lausanne, Switzerland

    Hayo Himmelrich, Alain Gumy, Heike Voigt, Pascal Launois & Jacques A. Louis

  5. Department of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Alan D. Levine

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Biedermann, T., Zimmermann, S., Himmelrich, H. et al. IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat Immunol 2, 1054–1060 (2001). https://doi.org/10.1038/ni725

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