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Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM.

The maintenance of FOXP3 expression in CD25(hi) regulatory T cells (Tregs) is crucial to the control of inflammation and essential for successful Treg transfer therapies. Coexpression of CD25 and FOXP3 in combination with a hypomethylated region within the FOXP3 gene, called the Treg-specific demethylated region (TSDR), is considered the hallmark of stable Tregs. The TSDR is an epigenetic motif that is important for stable FOXP3 expression and is used as a biomarker to measure Treg lineage commitment. In this study, we report that, unlike in peripheral blood, CD4(+) T cell expression of CD25 and FOXP3 is frequently dissociated at the inflamed site in patients with juvenile idiopathic arthritis, which led us to question the stability of human Tregs in chronic inflammatory environments. We describe a novel CD4(+)CD127(lo)CD25(hi) human T cell population that exhibits extensive TSDR and promoter demethylation in the absence of stable FOXP3 expression. This population expresses high levels of CTLA-4 and can suppress T conventional cell proliferation in vitro. These data collectively suggest that this population may represent a chronically activated FOXP3(lo) Treg population. We show that these cells have defects in IL-2 signaling and reduced expression of a deubiquitinase important for FOXP3 stability. Clinically, the proportions of these cells within the CD25(hi) T cell subset are increased in patients with the more severe courses of disease. Our study demonstrates, therefore, that hypomethylation at the TSDR can be decoupled from FOXP3 expression in human T cells and that environment-specific breakdown in FOXP3 stability may compromise the resolution of inflammation in juvenile idiopathic arthritis., (Copyright © 2014 The Authors.)

Objective: Granulocyte-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., Methods: Synovial 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., Results: The 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 (r(2) = 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., Conclusion: Our 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., (© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Children with systemic Juvenile Idiopathic Arthritis (sJIA), the most severe subtype of JIA, are at risk from destructive polyarthritis and growth failure, and corticosteroids as part of conventional treatment can result in osteoporosis and growth delay. In children where there is failure or toxicity from drug therapies, disease has been successfully controlled by T-cell-depleted autologous stem cell transplantation (ASCT). At present, the immunological basis underlying remission after ASCT is unknown. Immune reconstitution of T cells, B cells, natural killer cells, natural killer T cells and monocytes, in parallel with T-cell receptor (TCR) diversity by analysis of the β variable region (TCRVb) complementarity determining region-3 (CDR3) using spectratyping and sequencing, were studied in five children with sJIA before and after ASCT. At time of follow up (mean 11.5 years), four patients remain in complete remission, while one child relapsed within 1 month of transplant. The CD8(+) TCRVb repertoire was highly oligoclonal early in immune reconstitution and re-emergence of pre-transplant TCRVb CDR3 dominant peaks was observed after transplant in certain TCRVb families. Further, re-emergence of pre-ASCT clonal sequences in addition to new sequences was identified after transplant. These results suggest that a chimeric TCR repertoire, comprising T-cell clones developed before and after transplant, can be associated with clinical remission from severe arthritis., (© 2014 The Authors. Immunology published by John Wiley & Sons Ltd.)

In recent years, there have been many new developments in the field of regulatory T cells (Treg), challenging the consensus on their behaviour, classification and role(s) in disease. The role Treg might play in autoimmune disease appears to be more complex than previously thought. Here, we discuss the current knowledge of regulatory T cells through animal and human research and illustrate the recent developments in childhood autoimmune arthritis (juvenile idiopathic arthritis (JIA)). Furthermore, this review summarises our understanding of the fields and assesses current and future implications for Treg in the treatment of JIA.