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A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17

Abstract

Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-γ negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

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Figure 1: The generation of IL-17-producing T cells requires CD28 and ICOS costimulation.
Figure 2: Regulation of IL-17 expression by cytokines and transcriptional factors.
Figure 3: Regulation of IL-17 production by effector and memory T cells.
Figure 4: IL-17 regulates genes encoding inflammatory molecules.
Figure 5: IL-17 regulates chemokine expression in brain tissue during EAE.
Figure 6: Generation and analysis of Cc10-Il17–transgenic mice.

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Acknowledgements

We thank L. Glimcher and I.-C. Ho for Maf-transgenic mice; L. Glimcher and C. Wilson for T-bet-deficient mice; J. Elias for the Cc10 promoter construct; A. Farr for guidance in animal work; and the Dong lab for help and discussions. Supported by the National Institutes of Health (C.D.), Arthritis Foundation (S.H.C., R.N. and C.D.), Cancer Research Institute (C.D.) and MD Anderson Cancer Center (C.D.).

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Correspondence to Chen Dong.

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Supplementary information

Supplementary Fig. 1

Anti-IL-17 antibody specifically blocks IL-17 biological activity. (PDF 11373 kb)

Supplementary Fig. 2

Blockage of IL-17 after disease onset reduces inflammation during EAE. (PDF 7419 kb)

Supplementary Fig. 3

Summary of TH differentiation. (PDF 3099 kb)

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Park, H., Li, Z., Yang, X. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6, 1133–1141 (2005). https://doi.org/10.1038/ni1261

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