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The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF

Abstract

Interleukin 17 (IL-17)-producing helper T cells (TH17 cells) require exposure to IL-23 to become encephalitogenic, but the mechanism by which IL-23 promotes their pathogenicity is not known. Here we found that IL-23 induced production of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in TH17 cells and that GM-CSF had an essential role in their encephalitogenicity. Our findings identify a chief mechanism that underlies the important role of IL-23 in autoimmune diseases. IL-23 induced a positive feedback loop whereby GM-CSF secreted by TH17 cells stimulated the production of IL-23 by antigen-presenting cells. Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies TH17 cells as a crucial source of GM-CSF in autoimmune inflammation.

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Figure 1: IL-23 upregulates GM-CSF expression in TH17 cells.
Figure 2: IL-1β upregulates GM-CSF expression in TH17 cells.
Figure 3: Expression of TH17 cells markers is regulated by IL-1β and TNF.
Figure 4: Neutralization of GM-CSF attenuates adoptive EAE.
Figure 5: GM-CSF production by TH1 and TH17 cells is required for their encephalitogenicity.
Figure 6: Csf2−/− TH1 and TH17 cells infiltrate the CNS but do not induce EAE.
Figure 7: GM-CSF secreted by TH17 cells augments IL-23 production by CD11c+ cells.

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Acknowledgements

We thank KaloBios Pharmaceuticals for anti-GM-CSF; P. Gonnella for critical review; K. Regan for editorial assistance; and S. Yu for technical assistance. Supported by the US National Institutes of Health, the National Multiple Sclerosis Society and the M.E. Groff Foundation.

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M.E.-B. designed and did most of the experiments and wrote the manuscript; B.C. designed and did experiments, wrote the manuscript and supervised the study; H.D., Y.Y., M.C. and F.S. did experiments; G.-X.Z. wrote the manuscript; B.N.D. provided MBP(Ac1–11) TCR-transgenic and Csf2−/− mice; and A.R. designed experiments, wrote the manuscript and supervised the study.

Corresponding author

Correspondence to Abdolmohamad Rostami.

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El-Behi, M., Ciric, B., Dai, H. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12, 568–575 (2011). https://doi.org/10.1038/ni.2031

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