BackgroundInflammatory effector T cells trigger inflammation despite increased numbers of Treg cells in the synovial joint of patients suffering from juvenile idiopathic arthritis (JIA). The cAMP response element (CREM)α is known to play a major role in regulation of T cells in SLE, colitis, and EAE. However, its role in regulation of effector T cells within the inflammatory joint is unknown.MethodsCREM expression was analyzed in synovial fluid cells from oligoarticular JIA patients by flow cytometry. Peripheral blood mononuclear cells were incubated with synovial fluid and analyzed in the presence and absence of CREM using siRNA experiments for T cell phenotypes. To validate the role of CREM in vivo, ovalbumin-induced T cell dependent arthritis experiments were performed.ResultsCREM is highly expressed in synovial fluid T cells and its expression can be induced by treating healthy control PBMCs with synovial fluid. Specifically, CREM is more abundant in CD161+ subsets, than CD161− subsets, of T cells and contributes to cytokine expression by these cells. Finally, development of ovalbumin-induced experimental arthritis is ameliorated in mice with adoptively transferred CREM−/− T cells.ConclusionIn conclusion, our study reveals that beyond its role in SLE T cells CREM also drives an inflammatory phenotype of T cells in JIA.

The cAMP response element (CRE) modulator (CREM)α binds to genes promoters with CREs and regulates transcription via a chromatin-dependent mechanism. CREMα is important for the T cell pathophysiology of SLE suppressing IL-2 and CD3ζ transcription, but enhances IL-17. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of unknown origin. Th17 cells have a pathogenic role in arthritis and are not controlled by local FoxP3+ regulatory T cells (Tregs). Pathogenic T cells in the inflamed joints of JIA patients have enhanced expression of IL-17, IFNgamma and CD161. CD161+ CD4+ cells also contain FoxP3+ cells that produce proinflammatory cytokines. We observed enhanced CREM expression in JIA patient synovial fluid (SF) T cells and also after culture of healthy donor PBMCs with JIA SF. We furthermore found enhanced expression of CREM in CD4+CD161+ and in CD4+FoxP3+CD161+ cells, which produce inflammatory cytokines. Vice versa Helios+FoxP3+ cells, which are characteristically stable Tregs and do not express inflammatory cytokines, had lower levels of CREM. JIA SF induced IFNgamma, IL-17 and FoxP3 in T cells during incubation, which could be abrogated by CREM siRNA transfection. Within the FoxP3+ population, CREM siRNA reduced CD161+FoxP3+ cells but not Helios+FoxP3+ cells. We thus suggest CREMα overexpression in T cells contributes to T cell pathophysiology in JIA by regulating percentages of inflammatory CD4+ IL-17+ cells, as well as inflammatory CD161+FoxP3+ cells.

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