Possible CD25⁺CD4⁺ Treg suppression mechanisms in vivo. CD25⁺CD4⁺ Tregs may suppress their effector T cell targets (T_R) by a number of proposed mechanisms. In vivo CD25⁺CD4⁺ Tregs may act in a cell contact–dependent manner by competing directly for stimulatory ligands on the APC, by sinking essential growth factors such as IL-2, or by directly transmitting an as-yet uncharacterized negative signal. Alternatively, they may use longer-range suppressive mechanisms by means of the cytokines IL-10 and TGF-β. Finally, CD25⁺CD4⁺ Tregs may act through the APC either by triggering IDO activity, resulting in the generation of immunosuppressive metabolites, or by perturbing the APC’s presenting capacity. Such mechanisms are not necessarily mutually exclusive, and more than 1 might operate in tandem.