Inhibition of T Cell Proliferation by Macrophage Tryptophan Catabolism
Open Access
- 3 May 1999
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 189 (9), 1363-1372
- https://doi.org/10.1084/jem.189.9.1363
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-γ 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.Keywords
This publication has 56 references indexed in Scilit:
- The many roles of CD40 in cell-mediated inflammatory responsesImmunology Today, 1996
- Cooperative Role of Interferon Regulatory Factor 1 and p91 (STAT1) Response Elements in Interferon-γ-inducible Expression of Human Indoleamine 2,3-Dioxygenase GenePublished by Elsevier BV ,1996
- Localization of quinolinic acid in the murine AIDS model of retrovirus-induced immunodeficiency: implications for neurotoxicity and dendritic cell immunopathogenesisAIDS, 1996
- Molecular cloning, sequencing and expression of human interferon-γ-inducible indoleamine 2,3-dioxygenase cDNABiochemical and Biophysical Research Communications, 1990
- Contingent Genetic Regulatory Events in T Lymphocyte ActivationScience, 1989
- Human macrophages degrade tryptophan upon induction by interferon-gammaLife Sciences, 1987
- The glucose distribution in 9l rat brain multicell tumor spheroids and its effect on cell necrosisCancer, 1982
- PHA stimulation of human lymphocytes during amino acid deprivation. Protein, RNA and DNA synthesisJournal of Cellular Physiology, 1977
- A Facile Synthesis of 6-Chloro-d-tryptophanBulletin of the Chemical Society of Japan, 1975
- The Adaptive Increase of the Tryptophan Peroxidase-Oxidase System of LiverScience, 1951