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Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.

Terness P, Bauer TM, Röse L, Dufter C, Watzlik A, Simon H, Opelz G - J. Exp. Med. (2002)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, 69120 Heidelberg, Germany. peter_terness@med.uni-heidelberg.de

ABSTRACT
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.

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Effect of IDO-induced tryptophan metabolites on T cell proliferation. Peripheral lymphocytes were stimulated with anti-CD3 antibody for 3 d in the presence of various amounts (abscissa) of (A) 3-hydroxykynurenine, (B) anthranilic acid, (C) 3-hydroxyanthranilic acid, or (D) quinolinic acid. Positive control consisted of T cell stimulation in the absence of metabolites. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).
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fig7: Effect of IDO-induced tryptophan metabolites on T cell proliferation. Peripheral lymphocytes were stimulated with anti-CD3 antibody for 3 d in the presence of various amounts (abscissa) of (A) 3-hydroxykynurenine, (B) anthranilic acid, (C) 3-hydroxyanthranilic acid, or (D) quinolinic acid. Positive control consisted of T cell stimulation in the absence of metabolites. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).

Mentions: In vivo as well as in cell cultures, none of the tryptophan metabolites acts as a single component but in the presence of other metabolites. This prompted us to analyze the effect of metabolite mixtures. Fig. 8 A shows the action of kynurenine in combination with all other metabolites. It is evident that much smaller concentrations of kynurenine are required when combined with equal amounts of the other compounds (in combination: I50 = 15 μM, as single substance: I50 = 553 μM; Fig. 4 B). Even the combination of three or two active components enhances the effect of single substances (Fig. 8, B–D). For instance, whereas kynurenine is effective at 553 μM (Fig. 4 B) and 3-hydroxyanthranilic acid at 96 μM (Fig. 7 C) as single components, when combined (Fig. 8 D), 21 μM of each substance is sufficient to induce the same effect. Other combinations showed similar results, indicating that the metabolites add or even potentiate their respective effects.


Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.

Terness P, Bauer TM, Röse L, Dufter C, Watzlik A, Simon H, Opelz G - J. Exp. Med. (2002)

Effect of IDO-induced tryptophan metabolites on T cell proliferation. Peripheral lymphocytes were stimulated with anti-CD3 antibody for 3 d in the presence of various amounts (abscissa) of (A) 3-hydroxykynurenine, (B) anthranilic acid, (C) 3-hydroxyanthranilic acid, or (D) quinolinic acid. Positive control consisted of T cell stimulation in the absence of metabolites. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196057&req=5

fig7: Effect of IDO-induced tryptophan metabolites on T cell proliferation. Peripheral lymphocytes were stimulated with anti-CD3 antibody for 3 d in the presence of various amounts (abscissa) of (A) 3-hydroxykynurenine, (B) anthranilic acid, (C) 3-hydroxyanthranilic acid, or (D) quinolinic acid. Positive control consisted of T cell stimulation in the absence of metabolites. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).
Mentions: In vivo as well as in cell cultures, none of the tryptophan metabolites acts as a single component but in the presence of other metabolites. This prompted us to analyze the effect of metabolite mixtures. Fig. 8 A shows the action of kynurenine in combination with all other metabolites. It is evident that much smaller concentrations of kynurenine are required when combined with equal amounts of the other compounds (in combination: I50 = 15 μM, as single substance: I50 = 553 μM; Fig. 4 B). Even the combination of three or two active components enhances the effect of single substances (Fig. 8, B–D). For instance, whereas kynurenine is effective at 553 μM (Fig. 4 B) and 3-hydroxyanthranilic acid at 96 μM (Fig. 7 C) as single components, when combined (Fig. 8 D), 21 μM of each substance is sufficient to induce the same effect. Other combinations showed similar results, indicating that the metabolites add or even potentiate their respective effects.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, 69120 Heidelberg, Germany. peter_terness@med.uni-heidelberg.de

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus