[show abstract][hide abstract] ABSTRACT: We have recently shown that expression of the enzyme indoleamine 2, 3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the 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 combination of the T cell-derived signals IFN-gamma and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.
Journal of Experimental Medicine 06/1999; 189(9):1363-72. · 13.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: The mechanisms of induction and maintenance of tolerance in self-reactive T cells in the periphery are poorly understood. Current models assume that successful T cell activation only occurs if ligation of the T cell receptor (signal 1) by antigen presenting cells (APCs) is accompanied by a costimulatory signal (signal 2), and that signal 1 in the absence of signal 2 is either ignored or is tolerizing. However, there is also evidence for the existence of macrophages (M phi) capable of suppressing T cell activation both in vitro and in vivo. The possibility of a more actively induced tolerance exists, in which the M phi itself responds to T cell-mediated signals in a tolerogenic fashion. This would help to resolve the paradox that tissue M phi, which act as scavengers of self-antigen, can also act as professional APCs. The ability of tissue macrophages to actively suppress T cells would further underscore the importance of the innate immune system in regulating adaptive immune responses.
International Reviews Of Immunology 02/1999; 18(5-6):515-25. · 5.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.