The TGF-β/IDO axis in infectious tolerance.

An intricate network of molecular and cell regulators directs immune reactivity and immune surveillance through a complex process whereby antigen presented by specialized subsets of dendritic cells (DCs) will bias T cell responses towards immunity or tolerance. The choice depends both on the basic immunological program of distinct DC subsets and on environmental factors, resulting in complete flexibility of DC phenotype. Several soluble molecules (cytokines, amino acid metabolites, Toll-like receptor ligands) and membrane-anchored ligands (CTLA-4 and GITR) preside over the establishment of polarization of DC function. Among cytokines, TGF-beta exerts a suppressive control over immune reactivity, not only through actions on the T-cell compartment, but also via the autocrine and paracrine conditioning of DCs. In various DC subpopulations, TGF-beta signaling is directly linked to the induction of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme in a pathway resulting in a burst of regulatory kynurenines. The combined effects of tryptophan starvation and tryptophan catabolites induce a regulatory phenotype in naive CD4+ T cells, and triggers an IDO-based feed-forward loop between TGF-beta, IDO, and noncanonical NF-kappaB signaling necessary for sustaining regulatory T (Treg) function. This mechanism amplifies and sustains a network, known as ‘infectious tolerance’, that connects cytokines, DCs, and Treg cells in a functional interplay. Such suppressive state implies a TGF-beta/IDO/SHP1/2 axis whereby IDO functions as a signaling molecule. 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 may be an important mechanism of sustaining a long-term tolerance, that can be exploited therapeutically in controlling over-reacting immune responses and reinforcing tolerance in autoimmunity.