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RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

Abstract

Although the role of the TH1 and TH17 subsets of helper T cells as disease mediators in autoimmune neuroinflammation remains a subject of some debate, none of their signature cytokines are essential for disease development. Here we report that interleukin 23 (IL-23) and the transcription factor RORγt drove expression of the cytokine GM-CSF in helper T cells, whereas IL-12, interferon-γ (IFN-γ) and IL-27 acted as negative regulators. Autoreactive helper T cells specifically lacking GM-CSF failed to initiate neuroinflammation despite expression of IL-17A or IFN-γ, whereas GM-CSF secretion by Ifng−/−Il17a−/− helper T cells was sufficient to induce experimental autoimmune encephalomyelitis (EAE). During the disease effector phase, GM-CSF sustained neuroinflammation via myeloid cells that infiltrated the central nervous system. Thus, in contrast to all other known helper T cell–derived cytokines, GM-CSF serves a nonredundant function in the initiation of autoimmune inflammation regardless of helper T cell polarization.

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Figure 1: The ability of autoaggressive helper T cells to produce GM-CSF is dependent on IL-23 and is inhibited by IL-12 and IFN-γ.
Figure 2: GM-CSF-secreting autoaggressive helper T cells are highly encephalitogenic.
Figure 3: GM-CSF-secretion is essential for the pathogenicity of auto-aggressive helper T cells.
Figure 4: GM-CSF secretion alone renders helper T cells encephalitogenic.
Figure 5: GM-CSF produced by helper T cells is required during the effector phase of EAE, and preclinical CNS invasion of helper T cells is not impaired in the absence of GM-CSF.
Figure 6: GM-CSF produced by CNS-infiltrating helper T cells targets invading myeloid cells.
Figure 7: GM-CSF-secretion is dependent on RORγt expression and is inhibited by IL-27 in a dose-dependent way.

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Acknowledgements

We thank A. Waisman, S. Haak, M. Dreano and and M. Greter for critical review of the manuscript; I. Ivanov and D. Littman (New York University School of Medicine) for the plasmid RORγt-IRES-GFP; V. Kuchroo (Harvard University) for 2D2 mice; and Y. Iwakura (University of Tokyo) for Il17a−/− mice. Supported by the Swiss National Science Foundation (31003AB.131091 to B.B.), the Swiss Multiple Sclerosis Society (B.B. and T.S.), the Koetser Foundation (B.B.), Merck-Serono-Geneva (B.B.), Forschungskredit of the University of Zurich (L.C.) and Gemeinnützige Hertie–Stiftung (A.F.).

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B.B., L.C. and G.G. designed experiments, analyzed data and wrote the paper; L.C. and G.G. did the experiments; V.T. helped do the experiments; L.H., T.S. and A.F. designed, did and analyzed the experiments with the chimeric Csf2rb−/− mice; L.M. generated neutralizing chimeric monoclonal antibody to GM-CSF; and B.B. supervised the study.

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Correspondence to Burkhard Becher.

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L.M. is employed by Merck Serono S.A, which is involved in the discovery and commercialization of therapeutics for the prevention and treatment of human diseases.

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Codarri, L., Gyülvészi, G., Tosevski, V. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12, 560–567 (2011). https://doi.org/10.1038/ni.2027

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