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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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Tryptophan and kynurenine concentration in cultures of IDO-expressing DCs. Native DCs (control), DCs infected with IDO-adeno-GFP, IDO-adeno, or native replication-defective adenoviruses (control) were cultured in RPMI 1640 plus 10% FCS. Tryptophan (A) and kynurenine (B) concentrations were determined and the values (μM/105 cells) are shown on the ordinate.
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fig2: Tryptophan and kynurenine concentration in cultures of IDO-expressing DCs. Native DCs (control), DCs infected with IDO-adeno-GFP, IDO-adeno, or native replication-defective adenoviruses (control) were cultured in RPMI 1640 plus 10% FCS. Tryptophan (A) and kynurenine (B) concentrations were determined and the values (μM/105 cells) are shown on the ordinate.

Mentions: DCs were generated from blood monocytes in the presence of GM-CSF and IL-4, maturation was induced by TNF-α, and the phenotype was verified by FACS® analysis (18). These cells were infected with the recombinant IDO-adenoviruses. The efficiency of infection was monitored by expression of the green fluorescence marker protein harbored by the virus. Vital staining using FACS® analysis showed that DCs remained viable after adenoviral infection. It is known that IDO catalyzes the oxidation of tryptophan, resulting in kynurenine and other metabolites (21–23). To verify whether transgenic IDO exerted its catabolic effect, tryptophan as well as kynurenine were measured in cultures of DCs infected with IDO-adeno (Fig. 2, A and B) . As expected, the tryptophan concentration significantly decreased while kynurenine increased.


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)

Tryptophan and kynurenine concentration in cultures of IDO-expressing DCs. Native DCs (control), DCs infected with IDO-adeno-GFP, IDO-adeno, or native replication-defective adenoviruses (control) were cultured in RPMI 1640 plus 10% FCS. Tryptophan (A) and kynurenine (B) concentrations were determined and the values (μM/105 cells) are shown on the ordinate.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Tryptophan and kynurenine concentration in cultures of IDO-expressing DCs. Native DCs (control), DCs infected with IDO-adeno-GFP, IDO-adeno, or native replication-defective adenoviruses (control) were cultured in RPMI 1640 plus 10% FCS. Tryptophan (A) and kynurenine (B) concentrations were determined and the values (μM/105 cells) are shown on the ordinate.
Mentions: DCs were generated from blood monocytes in the presence of GM-CSF and IL-4, maturation was induced by TNF-α, and the phenotype was verified by FACS® analysis (18). These cells were infected with the recombinant IDO-adenoviruses. The efficiency of infection was monitored by expression of the green fluorescence marker protein harbored by the virus. Vital staining using FACS® analysis showed that DCs remained viable after adenoviral infection. It is known that IDO catalyzes the oxidation of tryptophan, resulting in kynurenine and other metabolites (21–23). To verify whether transgenic IDO exerted its catabolic effect, tryptophan as well as kynurenine were measured in cultures of DCs infected with IDO-adeno (Fig. 2, A and B) . As expected, the tryptophan concentration significantly decreased while kynurenine increased.

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