Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

Abstract

The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all caused by C. albicans species, host defense against C. albicans varies by anatomical location. T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19−/−) and IL-17R–deficient (IL-17RA−/−) mice experienced severe OPC, whereas Th1-deficient (IL-12p35−/−) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was impaired in IL-23p19−/− and IL-17RA−/−, but not IL-12−/−, mice, and TCR-αβ cells were more important than TCR-γδ cells. Surprisingly, mice deficient in the Th17 cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong induction of Th17 signature genes, including CXC chemokines and β defensin-3. Saliva from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.

Sensing of mammalian IL-17A regulates fungal adaptation and virulence

“…In line with what is observed in humans 7 , Candida overgrowth occurs under conditions of defective interleukin (IL)-17F 8 or IL-17RA signalling [8][9][10] , which suggests the importance of IL-17RA signalling in preventing infection. Under specific circumstances, IL-17A may, in fact, contribute to disease susceptibility in a host-autonomous fashion, perhaps by modifying the intrinsic virulence of the fungus 8 .…”

Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

“…Furthermore, we demonstrated that the fast homeostatic proliferation of CD4 + T N cells in MLNs critically contributes to the generation of gut-homing T EMphenotype Th17 cells, indicating an important role of the fast gutspecific proliferation. CD4 + T EM cells, including Th17 cells, represent a significant portion of the intestinal T cell population (27), and control bacterial infections in the gut (28,29). Therefore, the present results may further our understanding of gut-homing T EM cell differentiation in vivo.…”

“…Th17 cells produce the cytokine IL-17A, which is critically involved not only in protecting mucosal tissues from pathogenic infection (28,29) but also in pathogenesis for immune disorders, such as inflammatory bowel diseases (IBDs) and graft-versus-host disease (GVHD) (30). To understand Th17-mediated immune responses and its disorders, it is important to understand where and how these Th17 cells are generated.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…161 IL-23 promotes terminal differentiation and expansion of the Th17 cells, 162 and accumulating evidence indicates that Th17 cells are key cells in the response to C. albicans infection. 45,163,164 Th17 cells secrete numerous cytokines including IL-17A, IL-17F and IL-22, and play vital roles for immune protection against C. albicans at the majority of mucosal sites in the body. 165,166 The importance of Th17 cells in anti-Candida responses is not only portrayed by data from mice models, but also from human patients.…”