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dc.contributor.authorMunn, David H.
dc.contributor.authorShafizadeh, Ebrahim
dc.contributor.authorAttwood, John T.
dc.contributor.authorBondarev, Igor
dc.contributor.authorPashine, Achal
dc.contributor.authorMellor, Andrew L.
dc.date.accessioned2012-10-26T16:26:38Z
dc.date.available2012-10-26T16:26:38Z
dc.date.issued1999-05-3en_US
dc.identifier.citationJ Exp Med. 1999 May 3; 189(9):1363-1372en_US
dc.identifier.issn1540-9538en_US
dc.identifier.pmid10224276en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/552
dc.description.abstractWe 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.subjectArticlesen_US
dc.titleInhibition ofâ T Cell Proliferation by Macrophage Tryptophan Catabolismen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2193062en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Genetics
dc.contributor.corporatenameDepartment of Pediatrics
refterms.dateFOA2019-04-09T21:03:06Z
html.description.abstractWe 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.


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