Innate Lymphoid Cells: New Players in IL-17-Mediated Antifungal Immunity

The IL-17 cytokine family has emerged as a central component of the host immune system since its discovery two decades ago. IL17A and IL-17F, the two signature cytokines collectively referred to as IL-17 in the following, have attracted much attention owing to their pathological potential and their ability to promote autoimmune diseases such as psoriasis and rheumatoid arthritis. It has become clear however that IL-17 also plays a key role in host protection from infection with extracellular bacteria and fungi. IL-17A and IL-17F homoand heterodimers bind to a heterodimeric complex composed of IL-17RA and RC receptor subunits and trigger a signaling cascade that results in the activation of NF-kB and MAPK [1]. This results in the production of antimicrobial compounds and inflammatory mediators including G-CSF and CXC chemokines, which are believed to be the primary basis for recruitment and activation of neutrophils [1]. Recently, inborn errors in components of the IL-17 pathway have been associated with an increased susceptibility to fungal infections, first and foremost chronic mucocutaneous candidiasis (CMC). These include defects in the genes encoding IL-17F or IL17RA [2]. Genome-wide association studies with patients suffering from CMC have identified additional polymorphisms that cause defects in the IL-17 response [2], clearly indicating that the IL-17 pathway plays a non-redundant role in antifungal immunity. This notion is supported by studies using animal models: mice deficient in IL-17 signaling or unable to mount robust IL-17 production are strongly impaired to control skin and mucosal infections with Candida albicans [3,4]. In mice, IL-17 has also been shown to protect from other fungal infections including those caused by Pneumocystis carinii [5], Histoplasmacapsulatum [6], and Aspergillus fumingatus [7]. In line with its protective role at mucocutaneous surfaces, IL-17 acts mainly on epithelial cells of the skin and mucosal tissues. The cellular source of IL-17 however varies and depends on the inflammatory context and the site of infection.