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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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