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.

Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells

“…In contrast to mice, where numerous cytokines have been proposed to initiate GM-CSF transcription 8 , we observed that in humans, IL-2 is a particularly strong driver of GM-CSF production. In agreement with others, we found the GM-CSF-inducing capacity of IL-2 to be independent of the effect IL-2 has on proliferation 31 . Genome-wide association studies firmly link polymorphisms in the IL2RA locus with the risk to develop MS.…”

Producing GM-CSF: a unique T helper subset?

“…These results are in agreement with a recent study showing that STAT5-mediated signaling induced GM-CSF expression in human naïve and memory CD4 + T cells, whereas STAT3 signaling blocked it [6]. In fact, dysregulation of the IL-7/IL-7R axis has long been implicated in autoimmune diseases, such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis [7,8].…”

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

“…We observed a significantly higher frequency of GM-CSF-producing T cells in the pancreas of diabetic Tgfbr2 −/− than in diabetic Foxp3sf OT-II RIP-mOva mice. The TβRII-deficient T cells that produced GM-CSF also coexpressed high levels of IFN-γ, and these T cells are reminiscent of populations of IFN-γ + GM-CSF + T cells found to be enriched in the cerebrospinal fluid of multiple sclerosis patients and the synovial fluid of juvenile idiopathic arthritis patients (63)(64)(65). That this population of IFN-γ + GM-CSF + coproducers is preferentially increased in pancreas-infiltrating T cells from diabetic Tgfbr2 −/− OT-II RIP-mOva mice suggests that direct TGF-β control of T cells is particularly important in the regulation of GM-CSF production.…”