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 language | English (US) |
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Pages (from-to) | 1363-1372 |
Number of pages | 10 |
Journal | Journal of Experimental Medicine |
Volume | 189 |
Issue number | 9 |
DOIs | |
State | Published - May 3 1999 |
Keywords
- Indoleamine 2,3-dioxygenase
- Macrophage
- Macrophage colony-stimulating factor
- T cells
- Tryptophan
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology