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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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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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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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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DOI: https://doi.org/10.1038/ni.1883
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