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Abstract: 2-C-Substituted branched d-mannose analogues are novel monosaccharides, readily obtained from a Kiliani-acetonation sequence on d-fructose, followed by subsequent functional group manipulation. 2-C-Azidomethyl-d-mannose and 2-C-aminomethyl-d-mannose bind to the C-type lectin DC-SIGN (CD209) with significantly greater affinity than mannose. In particular, 2-C-aminomethyl-d-mannose exhibits a comparative 48-fold increase in binding as determined using a surface plasmon resonance-based competition assay. DC-SIGN is an important cell-surface type II transmembrane protein that interacts with blood group antigens, endogenous glycoproteins such as ICAM-3, and also deadly pathogens such as the human immunodeficiency and hepatitis C viruses. The effective use of small compounds to block target binding by mannose-selective C-type lectins at sub-millimolar concentrations has not been shown previously; thus, these data represent a very attractive thoroughfare to novel antiviral and immunomodulatory drug development. [Copyright &y& Elsevier]

γδ T cells are unconventional lymphocytes commonly described as ‘innate-like’ in function, which can respond in both a T cell receptor (TCR)-independent and also major histocompatibility complex (MHC)-unrestricted TCR-dependent manner. While the relative importance of TCR recognition had remained unclear, recent studies revealed that human Vδ1 T cells display unexpected parallels with adaptive αβ T cells. Vδ1 T cells undergo profound and highly focussed clonal expansion from an initially diverse and private TCR repertoire, most likely in response to specific immune challenges. Concomitantly, they differentiate from a Vδ1 T cell naïve (T naïve ) to a Vδ1 T cell effector (T effector ) phenotype, marked by the downregulation of lymphoid homing receptors and upregulation of peripheral homing receptors and effector markers. This suggests that an adaptive paradigm applies to Vδ1 T cells, likely involving TCR-dependent but MHC-unrestricted responses to microbial and non-microbial challenges. [ABSTRACT FROM AUTHOR]

Background & Aims Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored. Methods The phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli -exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1. Results Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin αEβ7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed α4β7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli -exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, and IL-17. Conclusions Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future. [ABSTRACT FROM AUTHOR]

Abstract: The Kiliani synthesis on the 4 readily accessible ketohexoses (d-fructose, d-tagatose, l-sorbose, d-psicose) allows access to 4 diastereomeric 2-C-methyl-aldohexoses (2-C-methyl-d-mannose, 2-C-methyl-d-talose, 2-C-methyl-l-gulose, 2-C-methyl-d-allose) and 4 diastereomeric 2-C-methyl-alditols (2-C-methyl-d-mannitol, 2-C-methyl-d-talitol, 2-C-methyl-l-gulitol, 2-C-methyl-d-allitol). Microbial oxidation of 2-C-methyl-d-mannitol and 2-C-methyl-l-gulitol gave 5-C-methyl-d-fructose; microbial oxidation of 2-C-methyl-d-talitol afforded 5-C-methyl-d-psicose, whereas 2-C-methyl-d-allitol formed 5-C-methyl-l-psicose. Both enantiomers of 5-C-methyl-fructose were equilibrated by d-tagatose-3-epimerase (DTE) with both enantiomers of 5-C-methyl-psicose. These transformations demonstrate that polyol dehydrogenases and DTE act on branched synthetic sugars. Full NMR analyses show that 5-C-methyl-d-fructose is present as the β-pyranose and β-furanose forms in a ratio of 90:10; all pyranose and furanose forms of 5-C-methyl-d-psicose are present in solution. The combination of chemical and biological procedures allows the environmentally friendly generation of a new family of branched monosaccharides. [Copyright &y& Elsevier]