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.
Issue Date
1999-05-3
Metadata
Show full item recordAbstract
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):1363-1372Related articles
- Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.
- Authors: Terness P, Bauer TM, Röse L, Dufter C, Watzlik A, Simon H, Opelz G
- Issue date: 2002 Aug 19
- FcepsilonRI induces the tryptophan degradation pathway involved in regulating T cell responses.
- Authors: von Bubnoff D, Matz H, Frahnert C, Rao ML, Hanau D, de la Salle H, Bieber T
- Issue date: 2002 Aug 15
- Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase.
- Authors: Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB
- Issue date: 2002 Aug 19
- Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase.
- Authors: Mellor AL, Chandler P, Baban B, Hansen AM, Marshall B, Pihkala J, Waldmann H, Cobbold S, Adams E, Munn DH
- Issue date: 2004 Oct
- Inhibition of allogeneic T-cell responses by dendritic cells expressing transduced indoleamine 2,3-dioxygenase.
- Authors: Funeshima N, Fujino M, Kitazawa Y, Hara Y, Hara Y, Hayakawa K, Okuyama T, Kimura H, Li XK
- Issue date: 2005 May