The 'T_reg paradox' in inflammatory arthritis

Classic regulatory T (T_reg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of T_reg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the T_reg paradox', we provide an overview of T_reg cell biology with a focus on T_reg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of T_reg cells while also promoting the differentiation of T_H17-like T_reg cell, exT_reg cell (effector T cells that were formerly T_reg cells), and osteoclastogenic T_reg cell subsets that mediate tissue injury. We present a new framework to understand T_reg cells in joint inflammation and define potential strategies for T_reg cell-directed interventions in human inflammatory arthritis.