Immune Regulation and Tolerance to Fungi in the Lungs and Skin

Abstract

The balance of pro- and anti-inflammatory signaling is a prerequisite for successful host/fungal interactions and requires the coordinate actions of both innate and adaptive immune systems. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases and limit protective antifungal immune responses. The newly described Th17 develop - mental pathway may play an inflammatory role previously attributed to uncontrolled Th1 responses and serve to accommodate the seemingly paradoxical association of chronic inflammatory responses with fungal persistence in the face of an ongoing inflammation. In this scenario, unrestricted fungal growth could result from the activation of not only pathogenic Th17 cells, but also Th2 cells whose activation is strictly dependent on fungal burden. The capacity of regulatory T cells (Tregs) to inhibit aspects of innate and adaptive antifungal immunity is required for protective tolerance to fungi. Indoleamine 2,3-dioxygenase (IDO) and tryptophan catabolites contribute to such a homeostatic condition by providing the host with immune defense mechanisms adequate for protection, without necessarily eliminating fungal pathogens - which would impair immune memory - or causing an unacceptable level of tissue damage. IDO and tryptophan metabolites may prove to be potent regulators capable of taming overzealous or heightened inflammatory host responses.