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

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

^*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.

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.