Inhibition of T cell proliferation by macrophage tryptophan catabolism.
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-gamma 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.
Munn
D H
DH
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA. dmunn@mail.mcg.edu
Shafizadeh
E
E
Attwood
J T
JT
Bondarev
I
I
Pashine
A
A
Mellor
A L
AL
D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D018920:Coculture Techniques; D003470:Culture Media; D004247:DNA / Q000096:biosynthesis; D016193:G1 Phase; D015870:Gene Expression; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*
D003470:Culture Media; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C028129:tryptophan methyl ester; D016173:Macrophage Colony-Stimulating Factor; D014364:Tryptophan; D004247:DNA; D014366:Tryptophan Oxygenase