Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction
- Gianluca Matteoli1,
- Elisa Mazzini1,
- Iliyan D Iliev1,
- Erika Mileti1,
- Francesca Fallarino2,
- Paolo Puccetti2,
- Marcello Chieppa1,
- Maria Rescigno1
- 1Department of Experimental Oncology, European Institute of Oncology, Milano, Italy
- 2Department of Experimental Medicine, University of Perugia, Perugia, Italy
- Correspondence to Dr Maria Rescigno, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, Milan 20141, Italy;
- Revised 24 November 2009
- Accepted 22 December 2009
Objective CD103+ gut dendritic cells (DCs) have been shown to be required for de novo conversion of adaptive T regulatory (Treg) cells. Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in tryptophan catabolism that is expressed by DCs isolated from tumour-draining lymph nodes. IDO-expressing DCs sustain and differentiate Tregs. The aim of this study was to investigate the expression and the possible physiological role of IDO in the tolerogenic properties of intestinal DCs.
Design The expression level of IDO in CD103+ and CD103− DCs was analysed by qRT-PCR, western blot and immunofluorescence. CD103+ and CD103− DCs were sorted from mesenteric lymph nodes (MLNs) and the small intestinal lamina propria, and the role of IDO in the conversion of Tregs and Th effector cell development was evaluated via specific inhibition or gene deletion. Oral tolerance, experimental colitis and T cell differentiation in vivo were assessed upon IDO inactivation.
Results We show that, primarily, CD103+ but not CD103− gut DCs express IDO whose inhibition results in reduced CD4+Foxp3+ T regulatory cell conversion and enhanced T cell proliferation. When IDO was inhibited or genetically deleted there was an increase in Th1 and Th17 differentiation both in vitro and in vivo. Finally, in vivo IDO blockade affected the development of Tregs specific for orally administered antigens, impaired oral tolerance induction and exacerbated colitis.
Conclusions We identified a new IDO-dependent pathway leading to acquisition of tolerogenic functions in mucosal CD103-expressing DCs, indicating IDO as a possible therapeutic target for gut disorders.
- CD103+ lamina propria dendritic cells
- indoleamine 2,3-dioxygenase
- T regulatory cells
- dendritic cells
- lamina proprial lymphocytes
- oral tolerance
- T lymphocytes
- dendritic cell
- regulatory T cell
- indoleamine 2,3-dioxygenase
- 1-methyl tryptophan
- dextran sodium sulfate
Funding This study was supported by the Crohn's and Colitis Foundation of America (to MR), by the European Research Council (to MR) and by the Italian Association for Cancer Research (to GM).
Competing interests None.
Ethics approval All experimental procedures using human cells complied with guidelines set by our review board after informed consent from the patients (European Institute of Oncology, Milan). Experiments using mice were performed according to the Principles of Laboratory Animal Care guidelines (directive 86/609/EEC) and approved by the Italian Ministry of Health.
Provenance and peer review Not commissioned; externally peer reviewed.