The 'Treg 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.