Hdl Handle:
http://hdl.handle.net/10675.2/552
Title:
Inhibition ofâ T Cell Proliferation by Macrophage Tryptophan Catabolism
Authors:
Munn, David H.; Shafizadeh, Ebrahim; Attwood, John T.; Bondarev, Igor; Pashine, Achal; Mellor, Andrew L.
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.
Citation:
J Exp Med. 1999 May 3; 189(9):1363-1372
Issue Date:
3-May-1999
URI:
http://hdl.handle.net/10675.2/552
PubMed ID:
10224276
PubMed Central ID:
PMC2193062
Type:
Article
ISSN:
1540-9538
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorMunn, David H.en_US
dc.contributor.authorShafizadeh, Ebrahimen_US
dc.contributor.authorAttwood, John T.en_US
dc.contributor.authorBondarev, Igoren_US
dc.contributor.authorPashine, Achalen_US
dc.contributor.authorMellor, Andrew L.en_US
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.en_US
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-
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