Regulatory T cells overturned: the effectors fight back

In the past 15 years, regulatory T cell (Treg) suppression has graduated from a phenomenon that 'dare not speak its name' to a field at the centre of a global research effort. It is now accepted that Tregs can target numerous cell populations to elicit potent immunosuppression. Intriguingly, emerging data suggest that certain signals can confer resistance to Treg suppression. Moreover, such resistance may be relevant to the pathogenesis of autoimmune diseases. In this article I review various pathways linked to resistance to Treg suppression. These include Toll-like receptor (TLR) signals, cytokines [in particular those that use the common gamma chain, such as interleukin (IL)-7 and IL-21] and the triggering of tumour necrosis factor (TNF) receptor family members (such as glucocorticoid induced tumor necrosis factor receptor (GITR), OX40 and 4-1BB). I also propose a model of 'tuned suppression' in which inflammatory stimuli and TLR ligation actively promote Treg function, such that as soon as effector cells re-acquire sensitivity to suppression the immune response can be efficiently curtailed.