IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells
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IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. / Noster, Rebecca; Riedel, René; Mashreghi, Mir-Farzin; Radbruch, Helena; Harms, Lutz; Haftmann, Claudia; Chang, Hyun-Dong; Radbruch, Andreas; Zielinski, Christina E.
In: SCI TRANSL MED, Vol. 6, No. 241, 18.06.2014, p. 241ra80.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells
AU - Noster, Rebecca
AU - Riedel, René
AU - Mashreghi, Mir-Farzin
AU - Radbruch, Helena
AU - Harms, Lutz
AU - Haftmann, Claudia
AU - Chang, Hyun-Dong
AU - Radbruch, Andreas
AU - Zielinski, Christina E
N1 - Copyright © 2014, American Association for the Advancement of Science.
PY - 2014/6/18
Y1 - 2014/6/18
N2 - 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.
AB - 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.
KW - Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
KW - Humans
KW - Interleukin-17/metabolism
KW - STAT3 Transcription Factor/metabolism
KW - Signal Transduction
KW - T-Lymphocytes, Helper-Inducer/metabolism
U2 - 10.1126/scitranslmed.3008706
DO - 10.1126/scitranslmed.3008706
M3 - SCORING: Journal article
C2 - 24944195
VL - 6
SP - 241ra80
JO - SCI TRANSL MED
JF - SCI TRANSL MED
SN - 1946-6234
IS - 241
ER -