Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells

By P. Terness, Thomas M. Bauer, Lars Röse, C. Dufter, A. Watzlik, Helmut Simon, G. Opelz. Journal of Experimental Medicine, 2002

1,012 citations recorded by the source corpus.

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.

Subfields: Biological Psychiatry, Immunology

View Paper: https://www.semanticscholar.org/paper/3f5f2b88b6a4f0f6276440ae13daab7ec7e1ff4a

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In Biological Psychiatry

1. D. Munn
2. A. Mellor
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In Immunology

1. D. Munn
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4. Guido Kroemer
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Citations in the corpus

• Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase (2003, background): “Some tryptophan catabolites induce apoptosis of T cells, primarily of CD4 + cell”
• Mesenchymal stem cells and immunomodulation: current status and future prospects (2016, background): “dendritic cells have also been shown to mediate the inhibitory effect of MSCs on T-cell proliferation.(41) NO is another soluble factor known to inhibit T-cell proliferation.”
• Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. (2006, methodology): “1 mg glutathione S-transferase–IkBa (1-317) substrate (Santa Cruz Biotech-”
• Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 (2013, background): “…step in tryptophan degradation and the combination of local reduction in tryptophan levels and production of bioactive tryptophan metabolites (kynurenine) appear to exert suppressive activity on T cells (Munn et al., 1998, 2005; Fallarino et al., 2002; Frumento et al., 2002; Terness et al., 2002).”
• Cancer despite immunosurveillance: immunoselection and immunosubversion (2006, background): “4c ), as well as promote the apoptosis of CD4 + T cell”
• The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells1 (2006, background): “Although the mechanisms of kynurenine action are largely unknown (17, 25, 53, 54), this observation clearly distinguishes the activity of IDO as a truly immunoregulatory enzyme from the effects on T cells of a mere starvation for amino acids, and paves the way to the possible use of synthetic kynure”
• Ido expression by dendritic cells: tolerance and tryptophan catabolism (2004, background): “Human T cells were also found to be sensitive to the anti-proliferative and cytotoxic effects of exogenously added kynurenine, picolinic acid and 3-hydroxy-anthranilic aci”
• Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. (2004, background): “antimicrobial (60, 61) and antiviral (62, 63) effects, and inhibition of T cell proliferation in some models (18, 25, 64); and (b) effects mediated by toxic downstream metabolites of tryptophan, which include CD4+ T cell apoptosis (65) and inhibition of T cell proliferation in other models (66, 67).”
• Dendritic cells: translating innate to adaptive immunity. (2006, background): “tential suppressive pathway inDCs entails the induction of active indoleamine dioxygenase, which can be toxic to lymphocytes [190–192].”