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The T helper type 2 response to cysteine proteases requires dendritic cell–basophil cooperation via ROS-mediated signaling

Nature Immunology volume 11, pages 608–617 (2010)Cite this article

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Abstract

The mechanisms that initiate T helper type 2 (TH2) responses are poorly understood. Here we demonstrate that cysteine protease–induced TH2 responses occur via 'cooperation' between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated TH2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the TH1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4+ basophils to the lymph node. Thus, the TH2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.

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Figure 1: Vital role of DCs in papain-induced TH2 responses.
Figure 2: DCs and basophils act in concert to drive TH2 responses.
Figure 3: ROS production by papain-activated DCs is critical for TH2 differentiation.
Figure 4: TSLP production in skin in response to immunization with papain is dependent on ROS.
Figure 5: Papain-induced TH2 responses are dependent on TLR4-TRIF signaling.
Figure 6: Regulation of basophil migration by ROS, TLR4 and TRIF signaling in DCs.

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Acknowledgements

We thank S.A. Mertens, L. Bronner and Y. Wang for assistance with cell sorting; Y. Wang, D. Levesque and D. Bonenberger for assistance with the maintenance of mice at the Emory Vaccine Center vivarium; S. Akira (Osaka University) for Tlr2−/−, Tlr3−/−, Tlr4−/−, Tlr6−/−, Tlr7−/−, Tlr9−/−, Myd88−/− and Ticam1lps−2/lps−2 mice; V. Dixit (Genentech) for Nalp3−/−, Ipaf−/− and Asc−/− mice; K.A. Hogquist (University of Minnesota) for Langerin-EGFP-DTR mice; and J. Witztum (University of California at San Diego) for EO6. Supported by the National Institutes of Health (U54AI057157, R37AI48638, R01DK057665, U19AI057266, HHSN266 200700006C, N01 AI50019, N01 AI50025) and the Bill & Melinda Gates Foundation.

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Authors and Affiliations

  1. Emory Vaccine Center, Atlanta, Georgia, USA

    Hua Tang, Weiping Cao, Sudhir Pai Kasturi, Rajesh Ravindran, Helder I Nakaya & Bali Pulendran

  2. Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA

    Kousik Kundu & Niren Murthy

  3. Center for Computational Immunology, Duke University, Durham, North Carolina, USA

    Thomas B Kepler

  4. Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale U631, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Université de la Méditerranée, Marseille, France

    Bernard Malissen

  5. Department of Pathology, Emory University, Atlanta, Georgia, USA

    Bali Pulendran

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Contributions

H.T. and B.P. designed experiments; H.T. did experiments; R.R. and W.C. assisted with experiments; S.P.K. K.K. and N.M. designed microparticles and assisted with ROS imaging; T.B.K. and H.L.N. assisted with data analyses.; B.M. provided mice; and H.T. and B.P. wrote the manuscript.

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Correspondence to Bali Pulendran.

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Tang, H., Cao, W., Kasturi, S. et al. The T helper type 2 response to cysteine proteases requires dendritic cell–basophil cooperation via ROS-mediated signaling. Nat Immunol 11, 608–617 (2010). https://doi.org/10.1038/ni.1883

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