Thus, an entirely new paradigm in immunology, and more specifically in immune tolerance, may be the coevolution of three systems, namely, the IDO1 mechanism, kynurenine-driven gene transcription, and T-cell regulatory activity, which, originating from the initial need of protecting the fetus in mammals, have later turned into a pivotal mechanism of peripheral tolerance in autoimmunity, transplantation, and neoplasia. This evidence concerns the gene IDO1 and Autoimmunity.