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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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Sensitivity of T, B, NK cells and DCs to tryptophan metabolites. T, B, and NK cells were separated from PBMCs and DCs were generated as described previously. The cells were incubated with a metabolite mixture (kynurenine plus 3-hydroxykynurenine plus anthranilic acid plus 3-hydroxyanthranilic acid plus quinolinic acid) (concentrations: 0, 8, 16, 32 μM for each metabolite). The percentage of dead cells (ordinate) was measured by 7-AAD-staining every day (abscissa).
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fig11: Sensitivity of T, B, NK cells and DCs to tryptophan metabolites. T, B, and NK cells were separated from PBMCs and DCs were generated as described previously. The cells were incubated with a metabolite mixture (kynurenine plus 3-hydroxykynurenine plus anthranilic acid plus 3-hydroxyanthranilic acid plus quinolinic acid) (concentrations: 0, 8, 16, 32 μM for each metabolite). The percentage of dead cells (ordinate) was measured by 7-AAD-staining every day (abscissa).

Mentions: In contrast to cell cultures, the exposure of lymphocytes to kynurenine derivatives “in vivo” is long-lasting. If the cytotoxic effect increases with time, even small amounts of metabolites may be effective. To test whether cytotoxicity is time dependent, purified T cells were incubated for 5 d with various amounts of tryptophan metabolites and the percentage of dead cells was determined daily (Fig. 10). The findings clearly show that the cytotoxic effect is time dependent and that even small amounts of substances become cytotoxic after an exposure time of several days. As shown in Fig. 11, B and C , this is also the case for B and NK cells.


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)

Sensitivity of T, B, NK cells and DCs to tryptophan metabolites. T, B, and NK cells were separated from PBMCs and DCs were generated as described previously. The cells were incubated with a metabolite mixture (kynurenine plus 3-hydroxykynurenine plus anthranilic acid plus 3-hydroxyanthranilic acid plus quinolinic acid) (concentrations: 0, 8, 16, 32 μM for each metabolite). The percentage of dead cells (ordinate) was measured by 7-AAD-staining every day (abscissa).
© Copyright Policy
Related In: Results  -  Collection

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

fig11: Sensitivity of T, B, NK cells and DCs to tryptophan metabolites. T, B, and NK cells were separated from PBMCs and DCs were generated as described previously. The cells were incubated with a metabolite mixture (kynurenine plus 3-hydroxykynurenine plus anthranilic acid plus 3-hydroxyanthranilic acid plus quinolinic acid) (concentrations: 0, 8, 16, 32 μM for each metabolite). The percentage of dead cells (ordinate) was measured by 7-AAD-staining every day (abscissa).
Mentions: In contrast to cell cultures, the exposure of lymphocytes to kynurenine derivatives “in vivo” is long-lasting. If the cytotoxic effect increases with time, even small amounts of metabolites may be effective. To test whether cytotoxicity is time dependent, purified T cells were incubated for 5 d with various amounts of tryptophan metabolites and the percentage of dead cells was determined daily (Fig. 10). The findings clearly show that the cytotoxic effect is time dependent and that even small amounts of substances become cytotoxic after an exposure time of several days. As shown in Fig. 11, B and C , this is also the case for B and NK cells.

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