Dendritic cells (DCs)-accessory cells capable of flexible programs in Ag presentation-are master regulators of immune responses and, depending on microenvironment stimuli, can bias T cell reactivity toward immunity or tolerance. Several soluble molecules (cytokines, amino acid metabolites, TLR ligands) and membrane-anchored ligands (CTLA-4 and GITR) preside over establishment of an activator or a suppressive phenotype in DCs. Among cytokines, transforming growth factor-beta (TGF-beta) exerts a suppressive control over immune reactivity, not only through actions on the T-cell compartment, but also via an autocrine and paracrine stimulation of DCs. In particular, these cells have been found to be both an early source and a target of TGF-beta actions. In DCs, autocrine, paracrine, and T-cell-derived TGF-beta activates the tolerogenic pathway of tryptophan catabolism-mediated by indoleamine 2,3-dioxygenase (IDO)-resulting in a burst of regulatory kynurenines which contribute to establishing a state of ‘infectious tolerance’. Nevertheless, treatment of mouse plasmacytoid DCs (pDCs) with TGF-beta confers also regulatory effects on IDO that are mechanistically separable from its enzymic activity. This novel function of IDO involves intracellular signaling events responsible for self-amplification and maintenance of a stably regulatory phenotype in pDCs. Therefore, the interplay between TGF-beta and IDO in DCs is an important mechanism of sustaining a long-term tolerance and their combined actions might be exploited in therapeutically opposing human pathologies characterized by over-reacting immune responses.
The role of TGF-beta as tolerogenic cytokine in regulating dendritic cell function.
BELLADONNA, Maria Laura;FALLARINO, Francesca;Pallotta M. T.;ORABONA, Ciriana;VOLPI, CLAUDIA;GROHMANN, Ursula;
2011
Abstract
Dendritic cells (DCs)-accessory cells capable of flexible programs in Ag presentation-are master regulators of immune responses and, depending on microenvironment stimuli, can bias T cell reactivity toward immunity or tolerance. Several soluble molecules (cytokines, amino acid metabolites, TLR ligands) and membrane-anchored ligands (CTLA-4 and GITR) preside over establishment of an activator or a suppressive phenotype in DCs. Among cytokines, transforming growth factor-beta (TGF-beta) exerts a suppressive control over immune reactivity, not only through actions on the T-cell compartment, but also via an autocrine and paracrine stimulation of DCs. In particular, these cells have been found to be both an early source and a target of TGF-beta actions. In DCs, autocrine, paracrine, and T-cell-derived TGF-beta activates the tolerogenic pathway of tryptophan catabolism-mediated by indoleamine 2,3-dioxygenase (IDO)-resulting in a burst of regulatory kynurenines which contribute to establishing a state of ‘infectious tolerance’. Nevertheless, treatment of mouse plasmacytoid DCs (pDCs) with TGF-beta confers also regulatory effects on IDO that are mechanistically separable from its enzymic activity. This novel function of IDO involves intracellular signaling events responsible for self-amplification and maintenance of a stably regulatory phenotype in pDCs. Therefore, the interplay between TGF-beta and IDO in DCs is an important mechanism of sustaining a long-term tolerance and their combined actions might be exploited in therapeutically opposing human pathologies characterized by over-reacting immune responses.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
