Regulatory T cells overturned: the effectors fight back

Abstract

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.

Figure 1

Model of tuned suppression: an immune response ‘primes’ the regulation required for its safe resolution. (a) High antigen dose, Toll-like receptor (TLR) ligation, cytokines and costimulation confer resistance to regulatory T cell (Treg) suppression in the context of infection. Many of these signals concomitantly enhance Treg suppression but their effects are largely resisted at this juncture. (b) As the pathogen load falls, the decreased density of presented antigen and loss of TLR-induced signals allow susceptibility to Treg suppression to be restored. The augmented Treg function conferred by proliferation and immune stimulation in (a) comes into play at this point to ensure efficient termination of the immune response. DC, dendritic cell; MHC, major histocompatibility complex; TNF, tumour necrosis factor.