Foxp3 Molecular Dynamics in Treg in Juvenile Idiopathic Arthritis

Abstract

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 minimize 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 Foxp3 dynamics 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 evaluated—leading 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 Foxp3 transcription and its post-translational control may open up tantalizing new avenues for immunotherapies to treat autoimmune arthritis.

Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

“…scRNA‐seq data were also generated on Tregs sorted from synovial fluid of patients with JIA, which complements prior detailed analyses of JIA synovial Treg phenotypes ( 43 ). Cytometric, imaging, and functional studies have demonstrated substantial heterogeneity of Tregs in JIA synovial fluid, including a subset of functional CD25 hi CD127 − Tregs that have downregulated FoxP3 expression ( 43 ) and subpopulations that differ in CD161 expression ( 44 ). Whether these Treg subpopulations can be discriminated transcriptomically remains to be demonstrated.…”

Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis—Insights From Other Diseases

“…The phenotype of CD4 + FOXP3 + Tregs in JIA has been considerably characterized in the past (6) with the molecular roles of FOXP3 in JIA reviewed by Copland and Bending in this special collection (7). It is now clear that the Treg TCR (T cell receptor) repertoire is highly restricted in JIA, both at the site of inflammation (8–11) and in circulation (10, 12).…”

Role of tumor-associated immune cells in prostate cancer: angel or devil?

“…Tregs, which were first reported by Sakaguchi et al 15 as a subset of T cells with a CD4 + CD25 - high phenotype, play an important role in regulating immune tolerance of the tumor microenvironment. Recent studies have found that FOXP3 + is also an important phenotype of Tregs 1617. Zhao et al 17 found that the number of Tregs obviously increases in the bone metastatic microenvironment of prostate cancer.…”