TGF-beta and kynurenines as the key to infectious tolerance

Abstract

The maintenance of self-tolerance is an integral part of the immune surveillance process, in which cytokines act as master regulators of a complex network involving multiple cell types. On such cytokines, transforming growth factor-beta (TGF-beta) exerts a suppressive control over immune reactivity, which so far appears to be mostly confined to the T-cell compartment. Recently, dendritic cells (DCs) have been found to be both an early source and a target of TGF-beta actions. In these cells, 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 that contribute to establishing a state of 'infectious tolerance'. Current molecular insights suggest a synergistic potential for TGF-beta and IDO in physiologically or therapeutically opposing human pathologies sustained by over-reacting immune responses.