IL-17-Driven Immune Signaling in Autoimmunity and Fungal Infections

Abstract

Interleukin (IL)-17 is a pro-inflammatory cytokine that is the founding member of a distinct subclass of cytokines (reviewed in Amatya et al., 2017). IL0-17 is produced by conventional Th17 cells as well as a variety of innate immune subtypes (gd-T cells, ILC3 and NKT cells, for example). IL-17 promotes immunity to extracellular microbes, particularly fungi. On the flip side, dysregulation of IL-17 expression or signaling promotes pathology in a variety of autoimmune settings, particularly plaque psoriasis. Consequently, biologic therapies targeting the IL-17/Th17 pathway have been used successfully in the clinic. Understanding how the balance between host defense and autoimmune inflammation is maintained remains a vital issue. Candida albicans is a commensal fungus responsible for opportunistic oropharyngeal candidiasis (OPC, thrush) in settings of immunodeficiency such as HIV/AIDS and chemotherapy. C. albicans also causes systemic and dermal infections. In recent years it has become evident that IL-17 is essential for protective immunity to C. albicans (Conti and Gaffen, 2015). In both mice and humans, T cell deficiencies and more specifically impairments in IL-17 receptor (IL-17R) signaling components (for example, IL-17RA, IL-17RC, Act1) are associated with chronic mucosal candidiasis. However, to date we lack a detailed understanding of the signaling components and effector activities of IL-17 that promote antifungal immunity. The IL-17R complex is ubiquitously expressed, and antifungal signaling by IL-17 has been documented in cells of mesenchymal and epithelial origin but also in hematopoietic cells. This talk will focus on multiple mechanisms by which IL-17 drives immunity to C. albicans, including (i) tissue-specific effects of IL-17 signaling, (ii) sources of IL-17 that drive immunity to mucosal candidiasis, and (iii) fungal-derived factors that drive IL-17 production in vivo in the context of infection.Amatya N, Garg AV, Gaffen SL. IL-17 signaling: The Yin and the Yang. Trends Immunol. 2017; 38:310-322.Conti HR, Gaffen SL. IL-17 and Candida albicans infections. J Immunol, 2015; 195:780-788. DisclosuresGaffen:Lycera: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Abbvie: Consultancy; UCB Celltech: Consultancy; Genentech: Speakers Bureau; Novartis: Consultancy.