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Helper T cells regulate type-2 innate immunity in vivo

Abstract

Type-2 immunity requires orchestration of innate and adaptive immune responses to protect mucosal sites from pathogens. Dysregulated type-2 responses result in allergy or asthma1. T helper 2 (TH2) cells elaborate cytokines, such as interleukin (IL)-4, IL-5, IL-9 and IL-13, which work with toxic mediators of innate immune cells to establish environments that are inhospitable to helminth or arthropod invaders2. The importance of TH2 cells in coordinating innate immune cells at sites of inflammation is not known. Here we show that polarized type-2 immune responses are initiated independently of adaptive immunity. In the absence of B and T cells, IL-4-expressing eosinophils were recruited to tissues of mice infected with the helminth Nippostrongylus brasiliensis, but eosinophils failed to degranulate. Reconstitution with CD4 T cells promoted accumulation of degranulated IL-4-expressing cells, but only if T cells were stimulated with cognate antigen. Degranulation correlated with tissue destruction, which was attenuated if eosinophils were depleted. Helper T cells confer antigen specificity on eosinophil cytotoxicity, but not cytokine responses, so defining a novel mechanism that focuses tissue injury at sites of immune challenge.

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Figure 1: Activation of interleukin (IL-4)-expressing cells in the absence of adaptive immunity.
Figure 2: Subsets of eosinophils identified by flow cytometry.
Figure 3: T helper cells regulate degranulation in vivo.
Figure 4: Tissue injury correlates with presence of both CD4 T cells and eosinophils.

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Acknowledgements

The authors thank M.-L. Wong for assistance with electron microscopy, C. McArthur for expertise with cell sorting, San Francisco General Hospital Histopathology Laboratory Service for tissue histology, N. Flores, L. Stowring and Z.-E. Wang for technical assistance, B. Seymour and R. Coffman for parasites, R. Venkayya, D. Erle and A. McKenzie for mice, and J. Bluestone, J. Cyster, M. Kuhns, L. Lanier and laboratory members for critically reading the manuscript. This work was supported in part by funding from National Institute of Allergy and Infectious Diseases and National Heart, Lung and Blood Institute, National Institutes of Health. K.S. is supported by the UCSF Medical Scientist Training Program. R.M.L. is an Ellison Senior Scholar in Global Infectious Diseases.

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Correspondence to Richard M. Locksley.

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Shinkai, K., Mohrs, M. & Locksley, R. Helper T cells regulate type-2 innate immunity in vivo. Nature 420, 825–829 (2002). https://doi.org/10.1038/nature01202

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