IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells

Although T helper 17 (T(H)17) 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 T(H)17 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 T-H cell subsets. Surprisingly, the induction of GM-CSF expression by human T-H cells is constrained by the interleukin-23 (IL-23)/ROR-gamma t/T(H)17 cell axis but promoted by the IL-12/T-bet/T(H)1 cell axis. IL-2-mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naive and memory T-H cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF+ T-H cells that coexpress interferon-g and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF-only-producing T-H cells that did not express T(H)1, T(H)2, and T(H)17 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 T(H)17 but instead with the T(H)1 axis.