Foxp3 Molecular Dynamics in Treg in Juvenile Idiopathic Arthritis
2018
Since the identification of the regulatory T-cell (Treg)-associated transcription factor
Foxp3, there have been intensive research efforts to understand its biology and roles in maintaining immune homeostasis. It is well established that thymic selection of a repertoire of self-reactive
Foxp3+ T-cells provides an essential mechanism to minimise reactions to self-antigens in the periphery, and thus aid in the prevention of autoimmunity. It is clear from both genetic and immunological analyses of juvenile idiopathic arthritis (JIA) patients that T-cells have a strong role to play in both the initiation and propagation of disease. The current paradigm is to view autoimmunity as a consequence of an imbalance between inflammatory and immunoregulatory mechanisms. This view has led to the assigning of cells and inflammatory mediators to different classes based on their assumed pro- or anti-inflammatory roles. This is typically reported as ratios of effector T-cells to Treg cells. Problematically, many analyses are based on static ‘snapshots-in-time’, even though both mouse models and human patient studies have highlighted the dynamic nature of
Foxp3+ T-cells in vivo, which can exhibit plasticity and time-dependent functional states. In this review, we discuss the role of
Foxp3dynamics in the control of T-cell responses in
childhood arthritis, by reviewing evidence in humans and relevant mouse models of inflammatory disease. Whilst the cellular dynamics of Treg have been well evaluatedleading to standard data outputs such as frequency, quantity and quality (often assessed by in vitro suppressive capacity) we discuss how recent insights into the molecular dynamics of
Foxp3transcription and its posttranslational control may open up tantalising new avenues for immunotherapies to treat
autoimmune arthritis.
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