C-Type Lectin Receptors Dectin-3 and Dectin-2 Form a Heterodimeric Pattern-Recognition Receptor for Host Defense against Fungal Infection

Abstract

C-type lectin receptors (CLRs) play critical roles as pattern-recognition receptors (PRRs) for sensing Candida albicans infection, which can be life-threatening for immunocompromised individuals. Here we have shown that Dectin-3 (also called CLECSF8, MCL, or Clec4d), a previously uncharacterized CLR, recognized α-mannans on the surfaces of C. albicans hyphae and induced NF-κB activation. Mice with either blockade or genetically deleted Dectin-3 were highly susceptible to C. albicans infection. Dectin-3 constantly formed heterodimers with Dectin-2, a well-characterized CLR, for recognizing C. albicans hyphae. Compared to their respective homodimers, Dectin-3 and Dectin-2 heterodimers bound α-mannans more effectively, leading to potent inflammatory responses against fungal infections. Together, our study demonstrates that Dectin-3 forms a heterodimeric PRR with Dectin-2 for sensing fungal infection and suggests that different CLRs may form different hetero- and homodimers, which provide different sensitivity and diversity for host cells to detect various microbial infections.

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

“…49 A recent study revealed that Dectin-3 recognized a-mannans on the surfaces of C. albicans hyphae and induced NF-kB activation in bone marrow-derived macrophages from C57B/L6 mice. 29 Dectin-3 constantly forms heterodimers with Dectin-2 for recognizing C. albicans hyphae. Compared to their respective homodimers, Dectin-3 and Dectin-2 heterodimers bound a-mannans more effectively, leading to potent inflammatory responses against fungal infections.…”

“…Compared to their respective homodimers, Dectin-3 and Dectin-2 heterodimers bound a-mannans more effectively, leading to potent inflammatory responses against fungal infections. 29 Another study indicated that Dectin-3 can mediate endocytosis. 113 Mincle, another C-type lectin, is expressed predominantly on macrophages.…”

“…Dectin-3-deficient mice are highly susceptible to C. albicans infection. 29 With a low dose of C. albicans infection, the survival rate of Dectin-3-deficient mice is significant lower than wild-type mice. But with a higher dose, only a slight difference was observed regarding the survival rate of wild-type mice and Dectin-3-deficient mice.…”

“…But with a higher dose, only a slight difference was observed regarding the survival rate of wild-type mice and Dectin-3-deficient mice. 29 MR-/-mice have also been used in studies. After challenging MR-/-mice and wild-type mice intraperitoneally with C. albicans, no significant difference was found in survival between the mice.…”

“…26,27 Of note, some CLRs are involved in the recognition of C. albicans, including Dectin-1, Dectin-2, Dectin-3 (originally named murine macrophage C-type lectin, MCL), the dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN), the macrophage mannose receptor (MR), Galectin-3, and the macrophage-inducible C-type lectin (Mincle). 28,29 Dectin-1 recognizes b-(1,3)-glucan, while the rest CLRs recognize different mannose-relative structures. 28 MBL is considered a soluble CLR.…”