The cell walls and capsules of
Cryptococcus neoformans
, a yeast-type fungal pathogen, are rich in polysaccharides. Dectin-2 is a C-type lectin receptor (CLR) that recognizes high-mannose polysaccharides. Previously, we demonstrated that Dectin-2 is involved in cytokine production by bone marrow-derived dendritic cells (BM-DCs) in response to stimulation with
C. neoformans
. In the present study, we analyzed the role of Dectin-2 in the phagocytosis of
C. neoformans
by BM-DCs. The engulfment of this fungus by BM-DCs was significantly decreased in mice lacking Dectin-2 (Dectin-2KO) or caspase recruitment domain-containing protein 9 (CARD9KO), a common adapter molecule that delivers signals triggered by CLRs, compared to wild-type (WT) mice. Phagocytosis was likewise inhibited, to a similar degree, by the inhibition of Syk, a signaling molecule involved in CLR-triggered activation. A PI3K inhibitor, in contrast, completely abrogated the phagocytosis of
C. neoformans
. Actin polymerization, i.e., conformational changes in cytoskeletons detected at sites of contact with
C. neoformans
, was also decreased in BM-DCs of Dectin-2KO and CARD9KO mice. Finally, the engulfment of
C. neoformans
by macrophages was significantly decreased in the lungs of Dectin-2KO mice compared to WT mice. These results suggest that Dectin-2 may play an important role in the actin polymerization and phagocytosis of
C. neoformans
by DCs, possibly through signaling via CARD9 and a signaling pathway mediated by Syk and PI3K.