Inhibition ofâ T Cell Proliferation by Macrophage Tryptophan Catabolism
dc.contributor.author | Munn, David H. | |
dc.contributor.author | Shafizadeh, Ebrahim | |
dc.contributor.author | Attwood, John T. | |
dc.contributor.author | Bondarev, Igor | |
dc.contributor.author | Pashine, Achal | |
dc.contributor.author | Mellor, Andrew L. | |
dc.date.accessioned | 2012-10-26T16:26:38Z | |
dc.date.available | 2012-10-26T16:26:38Z | |
dc.date.issued | 1999-05-3 | en_US |
dc.identifier.citation | J Exp Med. 1999 May 3; 189(9):1363-1372 | en_US |
dc.identifier.issn | 1540-9538 | en_US |
dc.identifier.pmid | 10224276 | en_US |
dc.identifier.uri | http://hdl.handle.net/10675.2/552 | |
dc.description.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 cellâ derived signals IFN-g 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. | |
dc.subject | Articles | en_US |
dc.title | Inhibition ofâ T Cell Proliferation by Macrophage Tryptophan Catabolism | en_US |
dc.type | Article | en_US |
dc.identifier.pmcid | PMC2193062 | en_US |
dc.contributor.corporatename | Institute of Molecular Medicine and Genetics | |
dc.contributor.corporatename | Department of Pediatrics | |
refterms.dateFOA | 2019-04-09T21:03:06Z | |
html.description.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 cellâ derived signals IFN-g 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. |