Immunosuppression via tryptophan catabolism: the role of kynurenine pathway enzymes.
Tryptophan catabolism occurring in dendritic cells (DCs) and initiated by indoleamine 2,3-dioxygenase (IDO) is an emerging major mechanism of peripheral tolerance. Here we provide evidence that: 1) tryptophan conversion to kynurenines is activated in DCs by cytotoxic T lymphocyte antigen 4, both in a soluble form or anchored to the regulatory T cell (Treg) membrane; 2) an increased IDO-dependent tolerogenesis correlates with the inhibition of DAP12 functions, an adapter molecule associated with activating receptors; 3) a tolerogenic phenotype can be acquired by DCs lacking functional IDO through the paracrine production of kynurenines by IDO-competent DCs; 4) the suppressive effect of Treg generated in a microenvironment with low tryptophan concentration and a mixture of kynurenines can protect mice in an experimental model of fulminant diabetes. Altogether, these data indicate that, in addition to tryptophan starvation induced by IDO activity, the paracrine production of kynurenines by enzymes downstream of IDO can also contribute to tolerogenesis in DCs, independently of tryptophan deprivation.
Belladonna
Maria Laura
ML
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, via del Giochetto, 06126 Perugia, Italy. laurabell@tin.it
Puccetti
Paolo
P
Orabona
Ciriana
C
Fallarino
Francesca
F
Vacca
Carmine
C
Volpi
Claudia
C
Gizzi
Stefania
S
Pallotta
Maria Teresa
MT
Fioretti
Maria Cristina
MC
Grohmann
Ursula
U
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D003713:Dendritic Cells / Q000378:metabolism; D003920:Diabetes Mellitus / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D019899:Paracrine Communication; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C484963:Tyrobp protein, mouse; D007737:Kynurenine; D014364:Tryptophan