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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 kynurenine on T cell proliferation induced by allogeneic DCs or anti-CD3 antibody. Peripheral lymphocytes were stimulated with (A) allogeneic DCs or (B) anti-CD3 mAb for 6 and 3 d, respectively. Various amounts of kynurenine (abscissa) were added to the cultures. Positive control was performed without kynurenine. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).
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fig4: Effect of kynurenine on T cell proliferation induced by allogeneic DCs or anti-CD3 antibody. Peripheral lymphocytes were stimulated with (A) allogeneic DCs or (B) anti-CD3 mAb for 6 and 3 d, respectively. Various amounts of kynurenine (abscissa) were added to the cultures. Positive control was performed without kynurenine. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).

Mentions: Previous studies came to the conclusion that tryptophan depletion is the mechanism by which IDO inhibits T cell activation (3, 14). An alternative mechanism would be that metabolites resulting from tryptophan breakdown influence T cell responsiveness. IDO-induced tryptophan degradation results in kynurenine, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, and quinolinic acid (21–23), whereby kynurenine is the main product. Therefore, we first tested the influence of kynurenine on the allogeneic T cell response. As shown in Fig. 4 A, l-kynurenine was able to completely inhibit the proliferation of T cells stimulated by allogeneic DCs (50% inhibition = I50: 157 μM). Moreover, l-kynurenine also suppressed proliferation of CD3-stimulated T cells (I50: 553 μM) (Fig. 4 B). The same effect was noted with D-kynurenine (unpublished data).


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 kynurenine on T cell proliferation induced by allogeneic DCs or anti-CD3 antibody. Peripheral lymphocytes were stimulated with (A) allogeneic DCs or (B) anti-CD3 mAb for 6 and 3 d, respectively. Various amounts of kynurenine (abscissa) were added to the cultures. Positive control was performed without kynurenine. 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

fig4: Effect of kynurenine on T cell proliferation induced by allogeneic DCs or anti-CD3 antibody. Peripheral lymphocytes were stimulated with (A) allogeneic DCs or (B) anti-CD3 mAb for 6 and 3 d, respectively. Various amounts of kynurenine (abscissa) were added to the cultures. Positive control was performed without kynurenine. T cell proliferation was determined by 3[H]thymidine incorporation (cpm) (ordinate).
Mentions: Previous studies came to the conclusion that tryptophan depletion is the mechanism by which IDO inhibits T cell activation (3, 14). An alternative mechanism would be that metabolites resulting from tryptophan breakdown influence T cell responsiveness. IDO-induced tryptophan degradation results in kynurenine, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, and quinolinic acid (21–23), whereby kynurenine is the main product. Therefore, we first tested the influence of kynurenine on the allogeneic T cell response. As shown in Fig. 4 A, l-kynurenine was able to completely inhibit the proliferation of T cells stimulated by allogeneic DCs (50% inhibition = I50: 157 μM). Moreover, l-kynurenine also suppressed proliferation of CD3-stimulated T cells (I50: 553 μM) (Fig. 4 B). The same effect was noted with D-kynurenine (unpublished data).

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