Regulatory CD4 T cells: sensing the environment

The immunosuppressive properties of naturally occurring regulatory T cells (Tregs) have classically been linked to an intrinsic state of hyporesponsiveness, yet, paradoxically, Tregs are phenotypically in an activated state and have intact proliferative capacity. In consideration of several recent biochemical reports on the intracellular signaling pathways operating in activated CD4(+)CD25(+) Tregs, we argue that the responsiveness of Tregs depends greatly on the local microenvironment. In particular, what influences Tregs to remain anergic or to proliferate arises from their ability to probe the extracellular milieu to respond to external stimuli for the modulation of intracellular signaling events, leading to very different quantitative and qualitative functional outcomes.