Brief Report: T Cell Expression of Granulocyte–Macrophage Colony‐Stimulating Factor in Juvenile Arthritis Is Contingent Upon Th17 Plasticity

Abstract

ObjectiveGranulocyte–macrophage colony stimulating factor (GM-CSF) is a potent inflammatory mediator that is responsible for recruitment and activation of innate immune cells. Recent data from murine studies have identified Th17 cells as a key source of GM-CSF and suggest that T cell–derived GM-CSF is instrumental in the induction of autoimmune disease. The present study was undertaken to analyze the expression of T cell–derived GM-CSF in the joints of patients with juvenile idiopathic arthritis (JIA) and to investigate the differentiation of Th17 cells and how this relates to GM-CSF+ T helper cells.MethodsSynovial fluid (SF) and peripheral blood (PB) samples from 24 patients with JIA were analyzed, by flow cytometry and reverse transcription–polymerase chain reaction, for expression of GM-CSF and the Th17 marker CD161. A cytokine capture assay was used to purify Th17 cells and test the plasticity of cytokine production in response to interleukin-12 (IL-12) and IL-23.ResultsThe frequency of GM-CSF–producing T helper cells was significantly enriched in SF mononuclear cells compared to PB mononuclear cells from the patients with JIA (24.1% of CD4+ T cells versus 2.9%) and closely correlated with the erythrocyte sedimentation rate (r2 = 0.91, P < 0.001). Synovial GM-CSF+ T cells were predominantly CD161+ and coexpressed interferon-γ (IFNγ), but not IL-17. Culture of Th17 cells in the presence of IL-12 led to rapid up-regulation of GM-CSF and IFNγ, recapitulating the phenotype of GM-CSF–expressing cells within the joint.ConclusionOur results identify a novel outcome of Th17 plasticity in humans that may account for the enrichment of GM-CSF–expressing T cells in the joints of patients with JIA. The association of GM-CSF expression with systemic inflammation highlights the potential role of Th17-related cytokines in the pathology of JIA.

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.…”

Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity

“…Autoimmune reactions may be triggered if inflammation is not resolved but dysregulated during the interaction of T cells with antigen-presenting cells. Freshly recruited monocytes, in particular, may respond to the milieu of cytokine signals generated by effector T-cell subsets typically driving autoimmunity [1,2,5,6]. We demonstrate that besides T cells expressing GM-CSF/IFN-γ being enriched in affected joints during JIA, also responder monocytes are present that become hyperactivated involving processes that include early activation-dependent cell death as a means of regulation.…”

“…As a consequence of chronic GM-CSF/IFN-γ costimulation, monocytes might undergo activation-dependent cell death as a counter mechanism eliminating overactivated cells. As the enrichment of GM-CSF/IFN-γ coexpressing CD4 + T cells in synovial fluid of JIA patients had been described [6], we speculated that GM-CSF/IFN-γ induced cell death of monocytes would also occur in vivo in arthritis joints. We thus analyzed cells from patients with active JIA, comparing peripheral blood and synovial fluid.…”

“…The precise mechanism by which GM-CSF promotes autoimmunity has not been described, but the existing literature identifies GM-CSF as a key cytokine by which Th17 cells might activate myeloid cells, thereby linking the adaptive with the innate immune system in autoimmunity [4]. These data were generated in mouse models and their relation to the human system is not fully established, but notably an enrichment of IFN-γ/GM-CSF coproducing cells within the Th17 population in the inflamed joints of children with JIA has recently been demonstrated [5,6]. Both IFN-γ and GM-CSF are potent inducers of monocyte activation.…”

T Cell-Derived GM-CSF, Regulation of Expression and Function

“…In human rheumatoid arthritis (RA), synovial CD4 + T cells were found to be a major source of GM-CSF that strongly promoted infDC differentiation [31]. In juvenile idiopathic arthritis, the frequency of GM-CSF-producing CD4 + T cells in synovial fluid was significantly correlated with GM-CSF protein level as well as serum erythrocyte sedimentation rate, an indicator of inflammation [32]. In a mouse model of human interstitial lung disease (ILD), there was increased infiltration of both GM-CSFproducing CD4 + T cells and TH17 cells into lung tissues [33].…”