title: IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells.
abstract: Although T helper 17 (TH17) cells have been acknowledged as crucial mediators of autoimmune tissue damage, the effector cytokines responsible for their pathogenicity still remain poorly defined, particularly in humans. In mouse models of autoimmunity, the pathogenicity of TH17 cells has recently been associated with their production of granulocyte-macrophage colony-stimulating factor (GM-CSF). We analyzed the regulation of GM-CSF expression by human TH cell subsets. Surprisingly, the induction of GM-CSF expression by human TH cells is constrained by the interleukin-23 (IL-23)/ROR-γt/TH17 cell axis but promoted by the IL-12/T-bet/TH1 cell axis. IL-2-mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naïve and memory TH cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF(+) TH cells that coexpress interferon-γ and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF-only-producing TH cells that did not express TH1, TH2, and TH17 signature cytokines or master transcription factors. Our findings demonstrate distinct and counterregulatory pathways for the generation of IL-17- and GM-CSF-producing cells and also suggest a pathogenic role for GM-CSF(+) T cells in the inflamed brain of multiple sclerosis (MS) patients. This provides not only a scientific rationale for depleting T cell-derived GM-CSF in MS patients but also multiple new molecular checkpoints for therapeutic GM-CSF suppression, which, unlike in mice, do not associate with the TH17 but instead with the TH1 axis.
authors.affiliation: Cellular Immunoregulation Group, Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Noster
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Riedel
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany.
authors.forename: Mir-Farzin
authors.initials: MF
authors.lastname: Mashreghi
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. Department of Neurology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Radbruch
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Harms
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haftmann
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany.
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Cellular Immunoregulation Group, Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Department of Neurology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. christina.zielinski@charite.de.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Zielinski
mesh_terms: D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor