School of Chemistry - Research Publications

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Author: Williams, Spencer × End date: 2015 × Start date: 2015 ×

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    Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism
    Cuskin, F ; Lowe, EC ; Temple, MJ ; Zhu, Y ; Cameron, EA ; Pudlo, NA ; Porter, NT ; Urs, K ; Thompson, AJ ; Cartmell, A ; Rogowski, A ; Hamilton, BS ; Chen, R ; Tolbert, TJ ; Piens, K ; Bracke, D ; Vervecken, W ; Hakki, Z ; Speciale, G ; Munoz-Munoz, JL ; Day, A ; Pena, MJ ; McLean, R ; Suits, MD ; Boraston, AB ; Atherly, T ; Ziemer, CJ ; Williams, SJ ; Davies, GJ ; Abbott, DW ; Martens, EC ; Gilbert, HJ (NATURE PUBLISHING GROUP, 2015-01-08)
    Yeasts, which have been a component of the human diet for at least 7,000 years, possess an elaborate cell wall α-mannan. The influence of yeast mannan on the ecology of the human microbiota is unknown. Here we show that yeast α-mannan is a viable food source for the Gram-negative bacterium Bacteroides thetaiotaomicron, a dominant member of the microbiota. Detailed biochemical analysis and targeted gene disruption studies support a model whereby limited cleavage of α-mannan on the surface generates large oligosaccharides that are subsequently depolymerized to mannose by the action of periplasmic enzymes. Co-culturing studies showed that metabolism of yeast mannan by B. thetaiotaomicron presents a 'selfish' model for the catabolism of this difficult to breakdown polysaccharide. Genomic comparison with B. thetaiotaomicron in conjunction with cell culture studies show that a cohort of highly successful members of the microbiota has evolved to consume sterically-restricted yeast glycans, an adaptation that may reflect the incorporation of eukaryotic microorganisms into the human diet.
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    Antigen Specificity of Type I NKT Cells Is Governed by TCR β-Chain Diversity
    Cameron, G ; Pellicci, DG ; Uldrich, AP ; Besra, GS ; Illarionov, P ; Williams, SJ ; La Gruta, NL ; Rossjohn, J ; Godfrey, DI (AMER ASSOC IMMUNOLOGISTS, 2015-11-15)
    NKT cells recognize lipid-based Ags presented by CD1d. Type I NKT cells are often referred to as invariant owing to their mostly invariant TCR α-chain usage (Vα14-Jα18 in mice, Vα24-Jα18 in humans). However, these cells have diverse TCR β-chains, including Vβ8, Vβ7, and Vβ2 in mice and Vβ11 in humans, joined to a range of TCR Dβ and Jβ genes. In this study, we demonstrate that TCR β-chain composition can dramatically influence lipid Ag recognition in an Ag-dependent manner. Namely, the glycolipids α-glucosylceramide and isoglobotrihexosylceramide were preferentially recognized by Vβ7(+) NKT cells from mice, whereas the α-galactosylceramide analog OCH, with a truncated sphingosine chain, was preferentially recognized by Vβ8(+) NKT cells from mice. We show that the influence of the TCR β-chain is due to a combination of Vβ-, Jβ-, and CDR3β-encoded residues and that these TCRs can recapitulate the selective Ag reactivity in TCR-transduced cell lines. Similar observations were made with human NKT cells where different CDR3β-encoded residues determined Ag preference. These findings indicate that NKT TCR β-chain diversity results in differential and nonhierarchical Ag recognition by these cells, which implies that some Ags can preferentially activate type I NKT cell subsets.
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