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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803277v1 183/1/145    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Brenk, M. Articles by von Bubnoff, D. PubMed PubMed Citation Articles by Brenk, M. Articles by von Bubnoff, D.

Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4⁺CD25⁺ Foxp3⁺ T Regulatory Cells¹

Manuela Brenk^*, Marina Scheler^*, Susanne Koch^*, Jürgen Neumann, Osamu Takikawa, Georg Häcker, Thomas Bieber^2,* and Dagmar von Bubnoff^2,3,*

^* Department of Dermatology and Allergy, Friedrich-Wilhelms-University of Bonn, Bonn, Germany; Institute of Genetics, Friedrich-Wilhelms-University of Bonn, Bonn, Germany; National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan; and Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany

Tryptophan catabolism through IDO activity can cause nonresponsiveness and tolerance acting on T cells. Given the crucial importance of dendritic cells (DCs) in the initiation of a T cell response, surprisingly little is known about the impact of IDO activity and tryptophan deprivation on DCs themselves. In the present study, we show that human DCs differentiated under low-tryptophan conditions acquire strong tolerogenic capacity. This effect is associated with a markedly decreased Ag uptake as well as the down-regulation of costimulatory molecules (CD40, CD80). In contrast, the inhibitory receptors ILT3 and ILT4 are significantly increased. Functionally, tryptophan-deprived DCs show a reduced capacity to stimulate T cells, which can be restored by blockade of ILT3. Moreover, ILT3^highILT4^high DCs lead to the induction of CD4⁺CD25⁺ Foxp3⁺ T regulatory cells with suppressive activity from CD4⁺CD25^– T cells. The generation of ILT3^highILT4^high DCs with tolerogenic properties by tryptophan deprivation is linked to a stress response pathway mediated by the GCN2 kinase. These results demonstrate that tryptophan degradation establishes a regulatory microenvironment for DCs, enabling these cells to induce T regulatory cells. The impact of IDO thus extends beyond local immune suppression to a systemic control of the immune response.

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 grant from the Deutsche Forschungsgemeinschaft (SFB 704/TP A15) and BONFOR.

² T.B. and D.v.B. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Dagmar von Bubnoff, Department of Dermatology and Allergy, Friedrich-Wilhelms-University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. E-mail address: d.bubnoff{at}uni-bonn.de

⁴ Abbreviations used in this paper: DC, dendritic cell; 7-AAD, 7-aminoactinomycin D; CHOP, C/EBP-homologous protein; iDC, immature DC; ILT, Ig-like transcript; mDC, mature DC; MFI, median fluorescence intensity; poly(I:C), polyriboinosinic-polyribocytidylic acid; rFI, relative fluorescence index; Treg, regulatory T cell; Trp, tryptophan; TT, tetanus toxoid.

⁵ The online version of this article contains supplemental material.