Studies in recent years have shown that the selective expression of indoleamine 2,3-dioxygenase (IDO) in certain cell populations may play an important role in mediating immunosuppression. Mechanistically, since IDO is a rate-limiting enzyme of the kynurenine pathway responsible for tryptophan catabolism, the prevailing explanation for its immunosuppressive action is based on the assumption that the presence of IDO in selected cell populations would consume local tryptophan and subsequently starve adjacent maternal T-cells of this essential amino acid. In this review, an alternative hypothesis is discussed, which suggests that IDO is mainly expressed in various types of antigen-presenting cells (such as placental syncytiotrophoblasts during pregnancy), and that its main function is to produce biologically-active tryptophan catabolites that will mediate immunosuppression. Mechanistically, because these tryptophan catabolites are concentrated in a microenvironment surrounding the IDO-expressing dendritic cells, they will selectively suppress the proliferation of a sub-population of T-cells that are activated by the allogeneic antigen-presenting cells and ultimately wipe out this T-cell sub-population. Evidence in support of this new mechanistic explanation is discussed. This hypothesis provides an alternative mechanistic explanation for the development of selective immune tolerance towards the allogeneic fetus during pregnancy. Moreover, it also offers insights into the functional role of certain tryptophan catabolites produced by cancer cells in evading the body's immune surveillance, as well as the potential usefulness of tryptophan catabolites as pharmacological agents for the induction of selective long-term immune tolerance towards the allogeneic organ transplant.

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