Using an Ancient Tool for Igniting and Propagating Immune Tolerance: IDO as an Inducer and Amplifier of Regulatory T Cell Functions

Although most CD4(+)CD25(+) regulatory T (T-reg) cells develop in the thymus (i.e., natural T-reg or nT(reg)), accumulating evidence suggests that they can also develop in the periphery (adaptive/induced T-reg or iT(reg)). Both types of cells are functionally associated with the expression of Foxp3, a transcription factor that is constitutively expressed in nT(reg) cells and inducible during iT(reg) cell generation from CD4(+)CD25(-) T lymphocytes. Multiple factors are involved in the generation and function of T-reg cells, but a major role seems to be played by indoleamine 2,3-dioxygenase (IDO). IDO can both deplete tryptophan in local tissue microenvironments and generate immunoregulatory catabolites, known as kynurenines. Tryptophan starvation and presence of kynurenines can induce the conversion of naive CD4(+)CD25(-) T cells into highly suppressive CD4(+)CD25(+)Foxp3(+) T-reg cells. In turn, T-reg cells induce IDO in dendritic cells (DCs) and convert inflammatory into regulatory DCs, which can further expand the T-reg cell compartment by tryptophan catabolism. Evidence suggests that the modulation of IDO activity favors the interconversion between T-reg cells and T helper type 17 (T(H)17) inflammatory cells. Thus, in the periphery, tolerogenic immune responses mediated by T-reg cells can be induced and amplified by IDO, a tryptophan catabolizing enzyme that also contributes to the plasticity of the T-reg cell lineage.