Macrophages can suppress T cell proliferation by degrading tryptophan through the enzyme indoleamine 2,3-dioxygenase (IDO). This process is induced by signals from T cells, such as IFN-γ and CD40 ligand. IDO expression in macrophages leads to tryptophan depletion, which inhibits T cell activation by causing a cell cycle arrest in mid-G1. T cells can exit this arrest only if they receive a second TCR signal in the presence of tryptophan. This mechanism allows antigen-presenting cells to regulate T cell activation by controlling tryptophan availability. The study shows that IDO expression by macrophages is crucial for preventing rejection of the allogeneic fetus during pregnancy. The findings suggest that IDO-mediated tryptophan catabolism is a key mechanism for maintaining peripheral tolerance and suppressing unwanted T cell responses. The results highlight the role of IDO in immune regulation and provide insights into how antigen-presenting cells can modulate T cell activity through tryptophan metabolism.Macrophages can suppress T cell proliferation by degrading tryptophan through the enzyme indoleamine 2,3-dioxygenase (IDO). This process is induced by signals from T cells, such as IFN-γ and CD40 ligand. IDO expression in macrophages leads to tryptophan depletion, which inhibits T cell activation by causing a cell cycle arrest in mid-G1. T cells can exit this arrest only if they receive a second TCR signal in the presence of tryptophan. This mechanism allows antigen-presenting cells to regulate T cell activation by controlling tryptophan availability. The study shows that IDO expression by macrophages is crucial for preventing rejection of the allogeneic fetus during pregnancy. The findings suggest that IDO-mediated tryptophan catabolism is a key mechanism for maintaining peripheral tolerance and suppressing unwanted T cell responses. The results highlight the role of IDO in immune regulation and provide insights into how antigen-presenting cells can modulate T cell activity through tryptophan metabolism.