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Foxp3⁺CD25⁺ T Regulatory Cells Stimulate IFN--Independent CD152-Mediated Activation of Tryptophan Catabolism That Provides Dendritic Cells with Immune Regulatory Activity in Mice Unresponsive to Staphylococcal Enterotoxin B¹

Pascal Feunou^*, Sophie Vanwetswinkel^*, Florence Gaudray^*, Michel Goldman^*, Patrick Matthys and Michel Y. Braun^2,*,

^* Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium; Laboratory of Immunobiology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; and Laboratory of Immunology, Faculty of Medicine, Université de Lille 2, Lille, France

Mice made unresponsive by repeated injection of staphylococcal enterotoxin B (SEB) contained SEB-specific CD25⁺CD4⁺TCRBV8⁺ T cells that were able to transfer their state of unresponsiveness to primary-stimulated T cells. About one-half of these cells stably up-regulated the expression of CD152. We undertook the present study to determine whether CD152^high cells seen in this system were T regulatory cells responsible for suppression or whether they represented SEB-activated CD4⁺ T effector cells. Our results show that, among SEB-specific TCRBV8⁺ T cells isolated from unresponsive mice, all CD152^highCD25⁺CD4⁺ T cells expressed Foxp3, the NF required for differentiation and function of natural T regulatory cells. Moreover, suppression by CD25⁺CD4⁺TCRBV8⁺ T cells was fully inhibited by anti-CD152 Abs. Following stimulation by soluble CD152-Ig, dendritic cells (DC) isolated from unresponsive mice strongly increased the expression and the function of indoleamine-2,3-dioxygenase (IDO), the enzyme responsible for the catabolism of tryptophan. This capacity to activate IDO was independent of IFN- production by DC because CD152-Ig stimulation of DC isolated from SEB-treated IFN--deficient animals activated IDO expression and function. Finally, adding 1-methyl-tryptophan, an inhibitor of tryptophan catabolism, increased substantially the capacity of DC from unresponsive animals to stimulate primary T cell response toward SEB. Thus, we conclude that IFN--independent CD152-mediated activation of tryptophan catabolism by Foxp3⁺CD25⁺ T regulatory cells provides DC with immune regulatory activity in mice unresponsive to SEB.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Télévie and the Fonds National pour la Recherche Scientifique of Belgium.

² Address correspondence and reprint requests to Dr. Michel Y. Braun, Institute for Medical Immunology, rue Adrienne Bolland 8, Gosselies, Belgium. E-mail address: mbraun{at}ulb.ac.be

³ Abbreviations used in this paper: IDO, indoleamine 2,3-dioxygenase; DC, dendritic cell; SEB, staphylococcal enterotoxin B; 1-MT, 1-methyl-tryptophan; SE, staphylococcal enterotoxin; Dn, division number.

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