Inhibition of T cell proliferation by macrophage tryptophan catabolism

We have recently shown that expression of the enzyme indoleamine 2,3-dioxyg enase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnan cy, IDO-expressing cells are widely distributed in primary and secondary ly mphoid organs. Here we show that monocytes that have differentiated under t he influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic comb ination of the T cell-derived signals IFN-gamma and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-media ted suppression. Purified T cells activated under tryptophan-deficient cond itions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 r eceptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptopha n to arrested cells was not sufficient to allow further cell cycle progress ion nor was costimulation via CD28. T cells could exit the arrested state o nly if a second round of T cell receptor signaling was provided in the pres ence of tryptophan. These data reveal a novel mechanism by which antigen-pr esenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vi vo allows them to suppress unwanted T cell responses.