MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 05/2011; 208(5):1041-53. DOI: 10.1084/jem.20100508
Source: PubMed


N-linked glycans are thought to protect class II major histocompatibility complex (MHC) molecules (MHCII) from proteolytic cleavage and assist in arranging proteins within the immune synapse, but were not thought to directly participate in antigen presentation. Here, we report that antigen-presenting cells (APCs) lacking native complex N-glycans showed reduced MHCII binding and presentation of the T cell activating glycoantigen (GlyAg) polysaccharide A from Bacteroides fragilis but not conventional peptides. APCs lacking native N-glycans also failed to mediate GlyAg-driven T cell activation but activated T cells normally with protein antigen. Mice treated with the mannosidase inhibitor kifunensine to prevent the formation of complex N-glycans were unable to expand GlyAg-specific T cells in vivo upon immunization, yet adoptive transfer of normally glycosylated APCs into these animals overcame this defect. Our findings reveal that MHCII N-glycosylation directly impacts binding and presentation of at least one class of T cell-dependent antigen.

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Available from: Jason A Bonomo, Aug 19, 2014
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    • "The antigens eliciting the highest frequencies of specific T cells producing IFN-γ are all involved in cell wall biosynthesis of Aspergillus, namely GEL1p and both glucans, partially in agreement with the results obtained in mice with IA, where GEL1p, CRF1p and α1–3 glucan resulted the antigens associated with a higher activation of type 1 responses [5]. The recognition of polysaccharides is probably mediated by specific T cells through the class II major histocompatibility complex (MHC) on APCs, as previously reported for other infectious agents showing glycoantigens, such as Staphylococcus aureus, Streptococcus pneumoniae and Bacteroides fragilis [14], [15]. Moreover, in our patients, the association between T cells producing IFN-γ to two or more antigens and a more favorable outcome may suggest that such protective T cells play a role in the resolution of the infection. "
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    ABSTRACT: Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, β1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA.
    PLoS ONE 09/2013; 8(9):e74326. DOI:10.1371/journal.pone.0074326 · 3.23 Impact Factor
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    • "Next to the DC-SIGN-mediated PSA binding at the molecular level, we show an enhanced binding of PSA to DC-SIGN expressing Raji cells over the parental cell line. Raji cells are frequently used as model for PSA internalization and presentation in MHC class II (Kalka-Moll et al., 2002; Cobb et al., 2004; Cobb and Kasper, 2008; Duan et al., 2008; Ryan et al., 2011). In our assays PSA internalization was also detectable in the parental cell line, however this could only be observed when cells were incubated with high concentrations of PSA. "
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    ABSTRACT: The zwitterionic capsular polysaccharide A (PSA) of Bacteroides fragilis is the first carbohydrate antigen described to be presented in major histocompatibility complex (MHC) class II for the induction of CD4(+) T cell responses. However, the identity of the receptor mediating binding and internalization of PSA in antigen presenting cells remains elusive. C-type lectins are glycan-binding receptors known for their capacity to target ligands for antigen presentation to T cells. Here, we investigated whether C-type lectins were involved in the internalization of PSA and identified dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as the main receptor for PSA on human dendritic cells (DC). The induction of PSA-specific T cell proliferation appeared to be completely dependent on DC-SIGN. These data reveal a crucial role for DC-SIGN in the endocytosis and routing of PSA in human DC for the efficient stimulation of PSA-specific CD4(+) T cells.
    Frontiers in Immunology 05/2013; 4:103. DOI:10.3389/fimmu.2013.00103
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    ABSTRACT: Over the past several years, there have been remarkable advances in our understanding of how commensal organisms shape host immunity. Although the full cast of immunogenic bacteria and their immunomodulatory molecules remains to be elucidated, lessons learned from the interactions between bacterial zwitterionic polysaccharides (ZPSs) and the host immune system represent an integral step toward better understanding how the intestinal microbiota effect immunologic changes. Somewhat paradoxically, ZPSs, which are found in numerous commensal organisms, are able to elicit both proinflammatory and immunoregulatory responses; both these outcomes involve fine-tuning the balance between T-helper 17 cells and interleukin-10-producing regulatory T cells. In this review, we discuss the immunomodulatory effects of the archetypal ZPS, Bacteroides fragilis PSA. In addition, we highlight some of the opportunities and challenges in applying these lessons in clinical settings.
    Immunological Reviews 01/2012; 245(1):13-26. DOI:10.1111/j.1600-065X.2011.01075.x · 10.12 Impact Factor
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