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Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity

Abstract

Interleukin 4 (IL-4) and IL-13 are critical for responses to parasitic helminthes. We used genetically engineered reporter mice to assess the temporal and spatial production of these cytokines in vivo. In lymph nodes, IL-4, but not IL-13, was made by follicular helper T cells (TFH cells). In contrast, tissue type 2 helper T cells (TH2 cells) produced both cytokines. There was also divergent production of IL-4 and IL-13 among cells of the innate immune system, whereby basophils produced IL-4, whereas innate helper type 2 cells (Ih2 cells) produced IL-13. IL-13 production by TH2 and Ih2 cells was dependent on the transcription factor GATA-3, which was present in large amounts in these cells, and in contrast to the small amount of GATA-3 in TFH cells and basophils. The distinct localization and cellular expression of IL-4 and IL-13 explains their unique roles during allergic immunity.

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Figure 1: Eosinophil recruitment, worm expulsion and antibody production during infection with N. brasiliensis after depletion of IL-13-producing cells.
Figure 2: Localization and number of cytokine-producing CD4+ T cells during parasitic infection.
Figure 3: Different production of IL-4 and IL-13 by TFH cells and canonical TH2 cells.
Figure 4: GATA-3 expression in IL-4- and IL-13-producing CD4+ T cells after infection with N. brasiliensis.
Figure 5: GATA-3 expression and cytokine production by CD4+ T cells in the absence of STAT6.
Figure 6: Production of IL-4 and IL-13 by innate type 2 effector cells after infection with N. brasiliensis.
Figure 7: Requirement for STAT6 and GATA-3 in cytokine production by innate type 2 effector cells.
Figure 8: GATA-3 is required for IL-13 expression, the recruitment of cells of the innate immune system and worm expulsion, but not for IgE production.

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Acknowledgements

We thank G. Kelsoe (Duke University) for the anti-NP IgG1 clone H33Lγ1/λ1; the US National Institutes of Health Tetramer Core for reagents; A. McKenzie (University of Cambridge, UK) and Z. Werb (University of California San Francisco) for mice; D. Ehrle and M. Ansel for review and comments; and N. Flores and Z. Wang for technical expertise. Supported by the National Institutes of Allergy and Infectious Diseases (AI026918, AI030663 and AI077439), the Howard Hughes Medical Institute and the Sandler Asthma Basic Research Center at the University of California San Francisco.

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H.-E.L., R.L.R. and R.M.L. conceived of the work; H.-E.L. generated IL-13 reporter mice; H.-E.L., R.L.R., J.K.B. and B.M.S. designed and/or did experiments; I.-C.H. contributed reagents; R.L.R. and R.M.L. wrote the manuscript.

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Correspondence to Richard M Locksley.

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Liang, HE., Reinhardt, R., Bando, J. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol 13, 58–66 (2012). https://doi.org/10.1038/ni.2182

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