Role of the 1,3-β-D-Glucan Receptor Dectin-1 in Fungal Infection and Activation of Innate and Anti-Tumor Immunity

Abstract

Fungal cell wall polysaccharides serve as target molecules for phagocytes, including macrophages, and neutrophils. These polysaccharides are specifically recognized by C-type lectins on the leukocytes. Dectin-1, a glycoprotein C-type lectin receptor for 1,3-β-glucans, is assumed to be involved in recognizing pathogenic fungi such as Candida albicans. However, the physiological role of Dectin-1 in innate immunity activation during the initial host defense and in some inflammatory diseases remains unclear. Therefore, it is crucial to investigate the contribution of this receptor to the immune system. By using Dectin-1-knockout mice and specific antibodies, we investigated the mechanisms by which Dectin-1 recognizes 1,3-β-glucan and activates innate and tumor immunity. Dectin-1 interacts with 1,3-β-glucosyl chains through a mechanism distinct from other C-type lectins. Dectin-1 activates NF-κB through cooperation with TLR2-mediated signaling and through the CARD9-mediated pathway independent of TLRs. NF-κB activation by Dectin-1 requires Trp-Ile-His sequence on the carbohydrate recognition domain and the cytoplasmic ITAM motif. In vivo study using Dectin-1-knockout mice and neutralizing antibodies revealed the crucial role of Dectin-1 in host defense against fungal infection and in antitumor activity modulated by β-glucan administration. In conclusion, Dectin-1 is an indispensable receptor for recognizing 1,3-β-glucans and for activating host immune systems against fungal invasion.