Dectin-2 Recognition of α-Mannans and Induction of Th17 Cell Differentiation Is Essential for Host Defense against Candida albicans

Abstract

Dectin-2 (gene symbol Clec4n) is a C-type lectin expressed by dendritic cells (DCs) and macrophages. However, its functional roles and signaling mechanisms remain to be elucidated. Here, we generated Clec4n(-/-) mice and showed that this molecule is important for host defense against Candida albicans (C. albicans). Clec4n(-/-) DCs had virtually no fungal alpha-mannan-induced cytokine production. Dectin-2 signaling induced cytokines through an FcRgamma chain and Syk-CARD9-NF-kappaB-dependent signaling pathway without involvement of MAP kinases. The yeast form of C. albicans induced interleukin-1beta (IL-1beta) and IL-23 secretion in a Dectin-2-dependent manner. In contrast, cytokine production induced by the hyphal form was only partially dependent on this lectin. Both yeast and hyphae induced Th17 cell differentiation, in which Dectin-2, but not Dectin-1, was mainly involved. Because IL-17A-deficient mice were highly susceptible to systemic candida infection, this study suggests that Dectin-2 is important in host defense against C. albicans by inducing Th17 cell differentiation.

C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1

“…Recently, Dectin-2 [36,37] has been shown to also be important for host response to C. albicans. Nevertheless, our finding sheds light on the cooperation of different and/or similar types of PRRs in innate responses.…”

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…Interleukin‐17 plays protective roles against bacterial and fungal infection by recruiting neutrophils, activating T cells and inducing antimicrobial peptides and inflammatory cytokines 1, 4, 578 or Mycobacterium bovis BCG infection 79.…”

“…It plays a crucial role in the host defence against bacterial and fungal infection by inducing pro‐inflammatory cytokines and chemokines, recruiting neutrophils, and activating T cells and B cells 1, 2. Mice deficient for IL‐17RA are highly susceptible to Klebsiella pneumoniae 3 and IL‐17‐deficient mice are susceptible to bacterial and fungal infection 4, 5. Interleukin‐17 is also implicated in various inflammatory/autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE), arthritis in IL‐1 receptor antagonist‐deficient (Il1rn –/– ) mice and imiquimod‐induced psoriatic dermatitis in mice 6, 7, 8, 9, 10.…”

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

“…138,140,141 Fungal recognition by Dectin-2 can induce the production of numerous cytokines, including TNF-a, IL-1Ra, IL-2, IL-10, IL-6, IL-1b, IL-12 and IL-23, and possibly cysteinyl leukotrienes. 49,51,142,143 Similarly, fungal recognition by Mincle induces the production of cytokines, including MIP-2, KC, IL-10 and TNF-a. 107,114 PRRs of dendritic cells (DCs)…”

“…[48][49][50] Of note, in the Syk signaling pathway, CARD9 plays a crucial role to induce cytokine induction. [51][52][53] Raf-1 is another kinase involved in CLRs signal transduction, which can be activated by Dectin-1 or DC-SIGN. 54,55 Interestingly, most PRRs, if not all, activate the transcription factor NF-kB or IRF3/7 to induce immune responses.…”