Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12.
DAP12 is an immunoreceptor tyrosine-based activation motif-bearing membrane adapter molecule expressed by different cell types. Although several receptors associate with DAP12 in murine dendritic cells (DC), the function of these receptors is as yet unknown. Here we report that splenic mature DC with DAP12 overexpression are characterized by an impaired tolerogenic potential. In contrast, inhibition of DAP12 function results in enhanced tolerogenesis and constitutive expression of immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO). Increased resistance to experimental encephalomyelitis is observed in DAP12 knockin mice, which is dependent on IDO expression. Therefore, DAP12-related receptors act as negative regulators of IDO-mediated tolerance in vivo.
Orabona
Ciriana
C
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
Tomasello
Elena
E
Fallarino
Francesca
F
Bianchi
Roberta
R
Volpi
Claudia
C
Bellocchio
Silvia
S
Romani
Luigina
L
Fioretti
Maria C
MC
Vivier
Eric
E
Puccetti
Paolo
P
Grohmann
Ursula
U
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014364:Tryptophan / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D016827:CD8 Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C484963:Tyrobp protein, mouse; D014364:Tryptophan