title: 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 T(H)1 and T(H)17 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.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Codarri
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyülvészi
authors.forename: Vinko
authors.initials: V
authors.lastname: Tosevski
authors.forename: Lysann
authors.initials: L
authors.lastname: Hesske
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.forename: Laurent
authors.initials: L
authors.lastname: Magnenat
authors.forename: Tobias
authors.initials: T
authors.lastname: Suter
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D006023:Glycoproteins; C486767:Il27 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D063308:Myelin-Oligodendrocyte Glycoprotein; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor