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Blockade of IDO Inhibits Nasal Tolerance Induction¹

Arnold P. J. van der Marel^*, Janneke N. Samsom, Mascha Greuter^*, Lisette A. van Berkel, Tom O’Toole^*, Georg Kraal^* and Reina E. Mebius^2,*

^* Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands; and Laboratory of Pediatrics, Division Gastroenterology, Erasmus Medical Center, Rotterdam, The Netherlands

The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4⁺ T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.

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 a VICI Program Grant 918.56.612 from the Netherlands Organization for Scientific Research (to R.E.M.).

² Address correspondence and reprint requests to Dr. Reina E. Mebius, Department of Molecular Cell Biology and Immunology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: r.mebius{at}vumc.nl

³ Abbreviations used in this paper: Treg, regulatory T cell; LN, lymph node; PLN, peripheral LN; CLN, cervical LN; DC, dendritic cell; pDC, plasmacytoid DC; 1-MT, 1-methyl-DL-tryptophan; MHCII, MHC class II; 7AAD, 7-aminoactinomycin D; DTH, delayed-type hypersensitivity.

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The JI 2007 179: 729-730. [Full Text]  

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