Microbial carbohydrate depolymerization by antigen-presenting cells: Deamination prior to presentation by the MHCII pathway

Department of Medicine, Channing Laboratory, Brigham and Women's Hospital and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/2008; 105(13):5183-8. DOI: 10.1073/pnas.0800974105
Source: PubMed

ABSTRACT After uptake by the endosome of an antigen-presenting cell (APC), exogenous proteins are known to be degraded into peptides by protease digestion. Here, we report the mechanism by which pure carbohydrates can be depolymerized within APC endosomes/lysosomes by nitric oxide (NO)-derived reactive nitrogen species (RNSs) and/or superoxide-derived reactive oxygen species (ROSs). Earlier studies showed that depolymerization of polysaccharide A (PSA) from Bacteroides fragilis in the endosome depends on the APC's having an intact inducible nitric oxide synthase (iNOS) gene; the chemical mechanism underlying depolymerization of a carbohydrate within the endosome/lysosome is described here. Examining the ability of the major RNSs to degrade PSA, we determined that deamination is the predominant mechanism for PSA processing in APCs and is a required step in PSA presentation to CD4(+) T cells by MHCII molecules. Structural characterization of the NO-derived product PSA-NO indicates that partial deaminative depolymerization does not alter the zwitterionic nature of PSA. Unlike native PSA, PSA-NO is presented by iNOS-deficient APCs to induce CD4(+) T cell proliferation. Furthermore, metabolically active APCs are required for PSA-NO presentation. In contrast to PSA degradation by RNSs, dextran depolymerization in the endosome depends on ROSs, including hydrogen peroxide- and superoxide-derived ROSs. This study provides evidence that MHCII pathway-mediated carbohydrate antigen processing in APCs is achieved by chemical reactions. RNSs and ROSs may be involved in the presentation of glycopeptides by MHC molecules via the processing of other carbohydrate-containing antigens, such as bacterial or viral glycoproteins or glycoconjugate vaccines.

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    • "This property of the PSA depended upon its zwitterionic character. Kasper provided an update of his laboratory's continuing efforts to delineate the molecular events associated with the processing of the zwitterionic PSA and its presentation to T cells [3]. After internalization by APC, the high molecular weight PSA traffics through the endosomal pathway and is subsequently processed into smaller fragments. "
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    • "However, either prolonging treatment of ZPS or dextran with exogenous ROS/RNS or increasing the ROS/RNS concentration results in formation of smaller degraded products in vitro. These data suggested that the ROS/RNS-induced depolymerization of polysaccharide is finely controlled in APCs (Duan et al. 2008). More recently, it has been shown that the oxidation of endocytosed PSA release protons which in turn inhibits the breakdown of PSA. "
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    ABSTRACT: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are constantly produced and are tightly regulated to maintain a redox balance (or homeostasis) together with antioxidants (e.g. superoxide dismutase and glutathione) under normal physiological circumstances. These ROS/RNS have been shown to be critical for various biological events including signal transduction, aging, apoptosis, and development. Despite the known beneficial effects, an overproduction of ROS/RNS in the cases of receptor-mediated stimulation and disease-induced oxidative stress can inflict severe tissue damage. In particular, these ROS/RNS are capable of degrading macromolecules including proteins, lipids and nucleic acids as well as polysaccharides, and presumably lead to their dysfunction. The purpose of this review is to highlight (1) chemical mechanisms related to cell-free and cell-based depolymerization of polysaccharides initiated by individual oxidative species; (2) the effect of ROS/RNS-mediated depolymerization on the successive cleavage of the glycosidic linkage of polysaccharides by glycoside hydrolases; and (3) the potential biological outcome of ROS/RNS-mediated depolymerization of polysaccharides.
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    ABSTRACT: Thus far, the best-studied and most appreciated biopolymers are the proteins. Although the investigation of proteins has been shown to be necessary for understanding of biological phenomena, more and more evidence shows that biological events cannot be explained solely by the functions of proteins. Fine tuning of the system requires the involvement of other biomolecules, such as carbohydrates and lipids. Key to our specific defense against microbial infections are critical interactions between the specific adaptive and relatively non-specific innate part of the immune response. The most critical link between both parts of the immune system is T cell activation by antigen presentation. This report describes the immunological significant role of bacterial-derived carbohydrate structures in T cell activation, as context of antigens as well as antigen itself. This report will expand the concepts of the role of carbohydrates in microbial interactions with the adaptive immune system.
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