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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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.).
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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