Cell's novel immune adjuvant mannan

Written by | Edited by Xue Yue | xi The interplay between innate and adaptive immunity in the immune system is critical for fighting infection, injury, and the pathogenesis of allergic and inflammatory diseases
.

Peripheral tissue infection or injury leads to activation of innate immune cells and migration to draining lymph nodes, thereby activating antigen-dependent adaptive immune responses
.

Stimuli with specific physical properties can directly enter the draining lymph nodes and directly activate resident innate and adaptive immune cells in the draining lymph nodes
.

However, it is unknown how lymph node innate immune responses induced by peripherally migrated cells differ from those induced directly by resident innate immune cells
.

Pathogen-associated molecular patterns are recognized by pattern recognition receptors (PRRs), and innate immune cells are activated.
This process is also critical for subsequent adaptive immune responses, so targeting PRRs has also been used in vaccine development
.

The C-type lectin receptors (CLRs) Dectin-1 and Dectin-2 in the PRR can recognize the cell wall polysaccharides β-glucan and mannose to regulate innate and adaptive immune responses in fungal infections
.

These fungal polysaccharides vary not only in chemical structure, but also in physical properties, including size, solubility, and more
.

Moreover, there are few studies on whether CLRs have potential as vaccine adjuvants
.

Recently, Ivan Zanoni's team from Harvard Medical School published an article entitled An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity in Cell
.

This study found that mannan from fungi can act as an immune adjuvant to improve the body's antibody response to viruses
.

The authors first isolated β-glucan and mannan from Candida albicans, which showed different physical properties, β-glucan was insoluble, with a diameter of 500 nm; mannan was soluble, with a diameter of 20 nm
.

β-glucan can induce macrophages to express cytokines and costimulatory molecules in vitro
.

Immobilization of mannan on microbeads can also activate Dectin2 on phagocytes
.

Beta-glucan induces skin abscesses and lesions after intradermal injection, whereas mannan does not
.

Transcriptome analysis of skin samples enriched for the type II interferon pathway
.

Mannan induced lymph node expansion, peripheral circulating leukocyte recruitment, and lymphocyte accumulation 6 hours after injection
.

In contrast, β-glucan-induced lymph node expansion occurred 24 hours later
.

The analysis found that mannan activates cells within the lymph nodes, leading to lymph node dilation, which is induced even in CCR7 knockout mice, where mannan rapidly accumulates
.

Lymph node transcriptome analysis Mannan induced responses earlier and more pronounced than β-glucans
.

Pathway analysis showed that mannan could upregulate both type I and type II IFN pathways
.

Flow analysis showed that CD8+ T and NK cells produced IFNg after mannan treatment in lymph nodes
.

In contrast, BATF3 knockout mice lacking cDC1 did not show impaired IFNγ expression
.

Blockade of type I interferon and IFNγ inhibited mannan-induced lymph node expansion and ISG expression
.

The authors used lipo-CpG, a TLR9 ligand capable of inducing lymph node expansion and ISG, but still failed to induce lymph node expansion and ISG expression in IFNa and IFNg receptor knockout mice
.

The authors used fluorescently labeled mannan analysis and found that they were mainly localized in CD11b+ CD11c+ envelope and sinusoidal macrophages, and most of them expressed CD169 as a marker
.

The authors found that the non-canonical NF-κB subunit RelB can regulate CD169+CD11b+CD11c+-induced lymph node innate immune responses
.

Further analyzing T cell proliferation, the authors found that mannose adjuvant-induced lymph node innate responses are also critical for adaptive immune responses
.

In order to adjust the physical properties of mannans, the authors formulated mannans with alum aluminum hydroxide, and the authors found that alum could adsorb 40% of the mannans
.

When injected into mice, alum-formulated mannose not only caused skin inflammation, but also entered the lymph nodes in a CCR7-independent manner, and induced a higher degree of lymph node expansion and a more pronounced increase in ISG
.

The authors next formulated SARS-CoV-2 spike protein with alum and mannose immunization to induce higher levels of type I immune responses and neutralizing antibodies against the spike protein with broad epitope specificity
.

Using this approach in a mouse model, alum-formulated mannans were found to enhance the body's response to multiple viral glycoproteins, upregulating the level and breadth of antibody responses
.

Original link: https://doi.
org/10.
1016/j.
cell.
2022.
01.
009 Publisher: 11th reprint notice [Original article] BioArt original article, welcome to forward and share personally, it is prohibited to reprint without permission, all the published articles The copyright of the work is owned by BioArt
.

BioArt reserves all legal rights and violators will be held accountable
.