Abstract
Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, β-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/β-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases.
Highlights
Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings
Toll-like receptor 2 (TLR2)−/− DCs displayed complete resistance to this activity (Fig. 7g). Taken together these results suggested that MGCP-mediated functional modifications of DCs in order to promote immune tolerance are largely mediated by two independent pattern recognition receptors (PRRs) pathways. induced Treg (iTreg) induction via Dectin[1] and Th1 suppression via TLR2
By identifying immunomodulatory components of the yeast cell wall and by evaluating their functional contributions toward pro- and anti-inflammatory immune responses, we significantly advance our basic understanding on the mechanisms by which the immune system communicates with resident microbiome, especially with commensal fungi
Summary
Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. Similar to fungal β-glucan, fungal mannan is reported to play immunomodulatory roles[7,16,17] Both pro- and anti-inflammatory roles of yeast-derived polysaccharides have been identified; precise structural specifications and mechanisms by which fungal polysaccharides modify the immune system remain largely unknown. Upon its removal by enzymatic interventions or through purification techniques, a relatively minor class of cell surface polysaccharides is unmasked that is capable of exerting potent anti-inflammatory effects on the immune system We named this mannan/β-1,6-glucan-containing polysaccharides (MGCP), which by facilitating the induction of Treg cells as well as by directly suppressing the IFN-γ producing Th1 cell differentiation, are capable of exerting potent immunosuppression toward multiple models of experimental autoimmune diseases. Mechanistic and structural specificities of MGCP highlight its therapeutic applicability against autoimmune diseases
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