Figure 8. Proposed hypothetical model of IDO-induced Treg activation based on synthesis of results from the in vitro models.

The interaction of resting Tregs with IDO⁺ pDCs results in activation of the Tregs through a combination of the GCN2 activation and tryptophan metabolites. Activated Tregs then suppress target T cells in an IDO-independent fashion, involving PD-ligand expression on the target DCs, and PD-1 expression (presumably on the target T cells). In addition, bystander CD4⁺ T cells responding to other antigens, if exposed to the conditions created by activating Tregs and IDO⁺ pDCs, are biased to differentiate into new Tregs.