Inhibition of T cell proliferation by macrophage tryptophan catabolism

David H. Munn, Ebrahim Shafizadeh, John T. Attwood, Igor Bondarev, Achal Pashine, Andrew L. Mellor

Research output: Contribution to journalArticle

1102 Scopus citations

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 oft 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.

Original languageEnglish (US)
Pages (from-to)1363-1372
Number of pages10
JournalJournal of Experimental Medicine
Volume189
Issue number9
DOIs
StatePublished - May 3 1999

Keywords

  • Indoleamine 2,3-dioxygenase
  • Macrophage
  • Macrophage colony-stimulating factor
  • T cells
  • Tryptophan

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Munn, D. H., Shafizadeh, E., Attwood, J. T., Bondarev, I., Pashine, A., & Mellor, A. L. (1999). Inhibition of T cell proliferation by macrophage tryptophan catabolism. Journal of Experimental Medicine, 189(9), 1363-1372. https://doi.org/10.1084/jem.189.9.1363