Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction.
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.


METHODS
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.
Matteoli
Gianluca
G
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, Milan, Italy.
Mazzini
Elisa
E
Iliev
Iliyan D
ID
Mileti
Erika
E
Fallarino
Francesca
F
Puccetti
Paolo
P
Chieppa
Marcello
M
Rescigno
Maria
M
D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D018928:Immunity, Mucosal; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D039001:Integrin alpha Chains / Q000032:analysis*; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D039001:Integrin alpha Chains; C091367:alpha E integrins; D010047:Ovalbumin