Abstract
The opportunistic fungal pathogen Candida albicans frequently causes diseases such as oropharyngeal candidiasis (OPC) in immunocompromised individuals. Although it is well appreciated that the cytokine IL-17 is crucial for protective immunity against OPC, the cellular source and the regulation of this cytokine during infection are still a matter of debate. Here, we directly visualized IL-17 production in the tongue of experimentally infected mice, thereby demonstrating that this key cytokine is expressed by three complementary subsets of CD90+ leukocytes: RAG-dependent αβ and γδ T cells, as well as RAG-independent ILCs. To determine the regulation of IL-17 production at the onset of OPC, we investigated in detail the myeloid compartment of the tongue and found a heterogeneous and dynamic mononuclear phagocyte (MNP) network in the infected tongue that consists of Zbtb46-Langerin- macrophages, Zbtb46+Langerin+ dendritic cells (DCs) and Ly6C+ inflammatory monocytes. Of those, the Langerin+ DC population stands out by its unique capacity to co-produce the cytokines IL-1β, IL-6 and IL-23, all of which promote IL-17 induction in response to C. albicans in the oral mucosa. The critical role of Langerin+ DCs for the innate IL-17 response was confirmed by depletion of this cellular subset in vivo, which compromised IL-17 induction during OPC. In conclusion, our work revealed key regulatory factors and their cellular sources of innate IL-17-dependent antifungal immunity in the oral mucosa.
Highlights
As part of the upper gastrointestinal tract, the oral cavity is colonized by microbes and constitutes an important entry point for hazardous pathogens
IL-17 is a key cytokine for immune homeostasis and host defense in barrier tissues, which can drive inflammatory diseases and immunopathology under certain conditions
Most studies addressing IL-17-mediated processes focus on the lower gastrointestinal tract, while other barrier tissues such as the oral mucosa remain largely understudied, despite their important role for entry of hazardous microbes
Summary
As part of the upper gastrointestinal tract, the oral cavity is colonized by microbes and constitutes an important entry point for hazardous pathogens. Oropharyngeal candidiasis (OPC) is a common infection of the oral cavity mediated by the opportunistic fungal pathogen Candida albicans in immunocompromised individuals [1]. It frequently develops as a consequence of impaired immune function due to administration of steroids and other immunosuppressant agents, or because of underlying diseases such as AIDS or primary immunodeficiencies [1]. The recent study of hereditary factors predisposing to OPC and other forms of mucocutaneous candidiasis determined the relevance of the interleukin-17 (IL-17) pathway as a key mechanism for protective immunity against this disease. Work on experimental mouse models further confirmed the important role of IL-17, in particular IL-17A and IL-17F, in antifungal defense [11,12,13]
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