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A mechanism for the initiation of allergen-induced T helper type 2 responses

Abstract

Both metazoan parasites and simple protein allergens induce T helper type 2 (TH2) immune responses, but the mechanisms by which the innate immune system senses these stimuli are unknown. In addition, the cellular source of cytokines that control TH2 differentiation in vivo has not been defined. Here we showed that basophils were activated and recruited to the draining lymph nodes specifically in response to TH2–inducing allergen challenge. Furthermore, we demonstrate that the basophil was the accessory cell type required for TH2 induction in response to protease allergens. Finally, we show that basophils were directly activated by protease allergens and produced TH2-inducing cytokines, including interleukin 4 and thymic stromal lymphopoietin, which are involved in TH2 differentiation in vivo.

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Figure 1: Active papain induces IgE secretion independently of TLR2, TLR4 or MyD88.
Figure 2: The protease activity of papain has adjuvant activity and leads to TH2 cell differentiation on day 4 after immunization.
Figure 3: Proteolytically active papain induces the migration of CD86hiCD11c+ cells and dermal DCs into draining lymph nodes.
Figure 4: Basophils enter the draining lymph node after immunization with papain and are necessary for TH2 differentiation.
Figure 5: The protease activity of papain induces the production of IL-4, tumor necrosis factor and IL-6 in bone marrow–derived basophils.
Figure 6: TSLP is required for basophil-mediated TH2 differentiation.

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Acknowledgements

We thank R. Locksley (University of California, San Fransisco) for sharing 4get mice; and S. Holley, C. Annicelli, N. Chu and S. Yu for technical assistance (Yale University). Il4ra−/− and DO11.10 × 4get mice and biotin-conjugated KJ1.26 were provided by K. Bottomly (Yale University). Supported by the National Institutes of Health (AI 055502 to R.M.), the Sandler Program for Asthma Research (R.M.) and the Howard Hughes Medical Institute (R.M.).

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Correspondence to Ruslan Medzhitov.

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Sokol, C., Barton, G., Farr, A. et al. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 9, 310–318 (2008). https://doi.org/10.1038/ni1558

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