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Fungal ?-glucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response.

ABSTRACT: ?-Glucans are naturally occurring polysaccharides in cereal grains, mushrooms, algae, or microbes, including bacteria, fungi, and yeast. Immune cells recognize these ?-glucans through a cell surface pathogen recognition receptor called Dectin-1. Studies using ?-glucans and other Dectin-1 binding components have demonstrated the potential of these agents in activating the immune cells for cancer treatment and controlling infections. In this study, we show that the ?-glucan from Saccharomyces cerevisiae induces the expression of immune regulatory cytokines (IL-10, TGF-?1, and IL-2) and a tolerogenic enzyme (IDO) in bone marrow-derived dendritic cells as well as spleen cells. These properties can be exploited to modulate autoimmunity in the NOD mouse model of type 1 diabetes (T1D). Treatment of prediabetic NOD mice with low-dose ?-glucan resulted in a profound delay in hyperglycemia, and this protection was associated with increase in the frequencies of Foxp3(+), LAP(+), and GARP(+) T cells. Upon Ag presentation, ?-glucan-exposed dendritic cells induced a significant increase in Foxp3(+) and LAP(+) T cells in in vitro cultures. Furthermore, systemic coadministration of ?-glucan plus pancreatic ? cell Ag resulted in an enhanced protection of NOD mice from T1D as compared with treatment with ?-glucan alone. These observations demonstrate that the innate immune response induced by low-dose ?-glucan is regulatory in nature and can be exploited to modulate T cell response to ? cell Ag for inducing an effective protection from T1D.

SUBMITTER: Karumuthil-Melethil S

PROVIDER: S-EPMC4170060 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Fungal β-glucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response.

Karumuthil-Melethil Subha S Gudi Radhika R Johnson Benjamin M BM Perez Nicolas N Vasu Chenthamarakshan C

Journal of immunology (Baltimore, Md. : 1950) 20140820 7

β-Glucans are naturally occurring polysaccharides in cereal grains, mushrooms, algae, or microbes, including bacteria, fungi, and yeast. Immune cells recognize these β-glucans through a cell surface pathogen recognition receptor called Dectin-1. Studies using β-glucans and other Dectin-1 binding components have demonstrated the potential of these agents in activating the immune cells for cancer treatment and controlling infections. In this study, we show that the β-glucan from Saccharomyces cere ...[more]

PMID: 25143443

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Project description:Anti-beta-glucan antibodies elicited by a laminarin-conjugate vaccine confer cross-protection to mice challenged with major fungal pathogens such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. To gain insights into protective beta-glucan epitope(s) and protection mechanisms, we studied two anti-beta-glucan monoclonal antibodies (mAb) with identical complementarity-determining regions but different isotypes (mAb 2G8, IgG2b and mAb 1E12, IgM). C. albicans, the most relevant fungal pathogen for humans, was used as a model.Both mAbs bound to fungal cell surface and to the beta1,3-beta1,6 glucan of the fungal cell wall skeleton, as shown by immunofluorescence, electron-microscopy and ELISA. They were also equally unable to opsonize fungal cells in a J774 macrophage phagocytosis and killing assay. However, only the IgG2b conferred substantial protection against mucosal and systemic candidiasis in passive vaccination experiments in rodents. Competition ELISA and microarray analyses using sequence-defined glucan oligosaccharides showed that the protective IgG2b selectively bound to beta1,3-linked (laminarin-like) glucose sequences whereas the non-protective IgM bound to beta1,6- and beta1,4-linked glucose sequences in addition to beta1,3-linked ones. Only the protective IgG2b recognized heterogeneous, polydisperse high molecular weight cell wall and secretory components of the fungus, two of which were identified as the GPI-anchored cell wall proteins Als3 and Hyr1. In addition, only the IgG2b inhibited in vitro two critical virulence attributes of the fungus, hyphal growth and adherence to human epithelial cells.Our study demonstrates that the isotype of anti-beta-glucan antibodies may affect details of the beta-glucan epitopes recognized, and this may be associated with a differing ability to inhibit virulence attributes of the fungus and confer protection in vivo. Our data also suggest that the anti-virulence properties of the IgG2b mAb may be linked to its capacity to recognize beta-glucan epitope(s) on some cell wall components that exert critical functions in fungal cell wall structure and adherence to host cells.

Dataset Information

Fungal ?-glucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response.

Publications

Fungal β-glucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response.

Similar Datasets

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