Th17 cells in immunity to Candida albicans

Abstract

Our understanding of immunity to fungal pathogens has advanced considerably in recent years. Particularly significant have been the parallel discoveries in the C-type lectin receptor family and the Th effector arms of immunity, especially Th17 cells and their signature cytokine, IL-17. Many of these studies have focused on the most common human fungal pathogen, Candida albicans, which is typically a commensal microbe in healthy individuals but causes various disease manifestations in immunocompromised hosts, ranging from mild mucosal infections to lethal disseminated disease. Here, we discuss emerging fundamental discoveries with C. albicans that have informed our overall molecular understanding of fungal immunity. In particular, we focus on the importance of pattern recognition receptor-mediated fungal recognition and subsequent IL-17 responses in host defense against mucosal candidiasis. In light of these recent advances, we also discuss the implications for anticytokine biologic therapy and vaccine development.

Figure 1

The Candida cell wall and PRRs that recognize subcomponents thereof. The yeast cell wall is composed of a variety of proteins and carbohydrates that serve as pathogen associated molecular patterns (PAMPs). These are recognized by PRRs in host cells and consequently induce inflammatory immune responses. The skeleton or the inner portion of the cell wall is mainly composed of chitin and β-(1,3)-glucan. Whereas β-(1,3)-glucan is recognized by Dectin-1, the receptor for chitin remains to be identified. The outer portion of the cell wall is comprised of mannoproteins and mannan, which are recognized by TLR4 and CLRs such as dectin-2, mincle and the mannose receptor. Engagement of appropriate PRRs by these cell wall molecular moieties results in the production of cytokines that shape anti-fungal immune responses.

Figure 2

PRR and Th17-based immunity to Candida albicans. A. PRRs including CLRs (dectin-1, dectin-2, mincle), TLRs (TLR2, 4) and inflammasomes (NLRP3, NLRC4, Caspase-8) respond to Candida PAMPs by inducing the NF-κB and MAPK pathways. B. PRRs in turn trigger expression and secretion of IL-6, IL-23 and IL-1β, which induce Th17 differentiation via the transcription factors STAT3 and RORγt. C. IL-17A and IL-17F produced by Th17 cells act on epithelial and mesenchymal cells to induce expression of neutrophil attracting chemokines (IL-8, CXCL1, CXCL5) and G-CSF, as well as AMPs such as defensins and S100 proteins.