Beta-glucan recognition by the innate immune system

Abstract

Beta-glucans are recognized by the innate immune system. This recognition plays important roles in host defense and presents specific opportunities for clinical modulation of the host immune response. Neutrophils, macrophages, and dendritic cells among others express several receptors capable of recognizing beta-glucan in its various forms. This review explores what is currently known about beta-glucan recognition and how this recognition stimulates immune responses. Special emphasis is placed on Dectin-1, as we know the most about how this key beta-glucan receptor translates recognition into intracellular signaling, stimulates cellular responses, and participates in orchestrating the adaptive immune response.

Figure 1:

The structure of β-glucan. Immunostimulatory microbial β-glucan is most commonly β-(1,3)-glucan with various degrees of β-(1,6)-glucan branching.

Figure 2:

The β-glucan receptor Dectin-1. Dectin-1 consists of an extracellular C-type lectin domain for β-(1,3)-glucan detection, linked via a transmembrane domain to an intracellular signaling tail. A stalk region linking the C-type lectin domain to the transmembrane domain is present in some isoforms. The stalk region of human Dectin-1 (full length only) and the C-type lectin domain of murine Dectin-1 are glycosylated.

Figure 3:

Fungal morphology can influence the ability of Dectin-1 to recognize β-glucan in cell walls. A) Candida albicans can grow in a budding yeast form, or a filamentous form. During budding growth, cell separation results in the formation of bud and birth scars in the cell wall which expose the β-glucan core to recognition by the receptor. During filamentous growth, the core β-glucan layer is obscured by the outer layer (mostly mannan). B) Aspergillus fumigatus also exists in several morphological stages, but the sequence of β-glucan exposure is quite different. Aspergillus spores have hard waxy coating that covers β-glucan, and the spores are thus not recognized by Dectin-1. When activated, the spores swell, germinate, and grow as long branched hyphae. β-glucan in the cell wall is exposed once the spores begin to swell and is readily accessible to Dectin-1 in the filament cell walls.

Figure 4:

ITAM-like signaling by Dectin-1. The conventional model of ITAM signaling requires phosphorylation (by Src family kinases) of two appropriately-spaced tyrosines on a receptor tail. These phospho-tyrosines serve as binding sites for the two SH2 domains of Syk. The cytoplasmic tail of Dectin-1 requires only one phospho-tyrosine to signal via Syk. The “hemITAM” model proposes that the two SH2 domains of Syk can bind to two phospho-tyrosines on appropriately clustered Dectin-1 molecules.

Figure 5:

Dectin-1 signal transduction. Dectin-1 signaling via Src and Syk kinases triggers phagocytosis and respiratory burst activity. Dectin-1 signals also control the inflammatory response by activating transcription factors, including NFAT and the canonical and non-canonical NF-κB family members. The signaling adaptor CARD9 participates in signaling downstream of Dectin-1 in two ways. First, it enhances TLR-induced responses, likely through activation of MAP kinases. Second, in specific myeloid cell populations CARD9 directly promotes activation of NF-κB.