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: 13.91). 05/2011; 208(5):1041-53. DOI: 10.1084/jem.20100508
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Fucosylation catalyzed by fucosyltransferases (FUTs) is an important post-translational modification involved in a variety of biological processes. The purpose of the current study is to determine the roles of fucosylation in rheumatoid arthritis (RA) and the efficacy of reestablishing the immune homeostasis by using 2-Deoxy-D-galactose (2-D-gal), a fucosylation inhibitor.Methods: Q-PCR was performed to determine the expression of fucosyltransferases (FUTs) in RA and osteoarthritis (OA) synovial tissues and FACS sorted cells from RA synovial fluids. The in vivo inhibitory effect of 2-D-gal was evaluated in a collagen-induced arthritis (CIA) model. The in vitro effects of 2-D-gal on inflammatory macrophage differentiation, cytokine production, antigen uptake, processing, and presenting functions were analyzed.Results: FUTs that are involved in terminal or sub-terminal, but not core or O-fucosylation, were upregulated in RA, compared to OA synovial tissues. The expression of terminal FUTs was highly positively correlated with that of TNF encoding for tumor necrosis factor α. Terminal FUTs were predominately expressed in M1 macrophages. In vivo, 2-D-gal treatment precluded CIA development with reduced inflammatory macrophages and Th17 in draining lymph nodes, decreased TNF-α, IL-6 and antibodies to type II collagen in the serum. In vitro, 2-D-gal skewed the differentiation of M1 macrophages to IL-10 producing M2 macrophages. Furthermore, 2-D-gal significantly inhibited antigen presenting function of M1 macrophages.Conclusion: Terminal fucosylation is a novel hallmark of inflammatory macrophages. Inhibition of terminal FUTs reshapes the differentiation and functions M1 macrophages, leading to resolution of inflammation in arthritis. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 05/2014;
  • Source
    American Journal of Transplantation 01/2014; · 6.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Common variable immunodeficiency (CVID), the most frequent symptomatic primary immune deficiency in humans, is a heterogeneous group of immunologic disorders estimated to affect 1:10,000-1:50,000. Although a clear disease etiology remains elusive, a common characteristic of CVID is deficient IgG Ab production in response to infection or vaccination. Patients often also exhibit autoimmune cytopenias with symptoms of abnormal T cell function, including reductions in naive T cells, which correlate with clinical severity. In this study, we discovered that targeted alterations in the glycome of the myeloid lineage lead to spontaneous immunodeficiency characteristic of both humoral and T cell dysfunction regularly found in human CVID. Mice carrying a myeloid-specific knockout of the Mgat2 gene encoding UDP-GlcNAc:α-6-d-mannoside β-1,2-N-acetylglucosaminyltransferase II enzyme exhibit deficiencies in IgG responses to both protein and polysaccharide conjugate vaccines. Interestingly, the immunodeficiency is associated with decreased T cell activity because of a persistent autoimmune-mediated depletion of naive T cells, which is induced by changes in erythrocyte surface glycosylation. The N-glycosylation dependent autoepitopes that emerge on erythrocytes lead to autoimmune hemolytic anemia, and the causative auto-IgM cross-reacts with naive T cells despite the lack of glycan change on T cells. These findings demonstrate that alterations in erythrocyte glycosylation trigger the development of autoantibodies directed at both erythrocytes and naive T cells, revealing a possible mechanistic link between the induction of autoimmune hemolytic anemia, the reduction in naive T cells, and poor Ab responses to vaccine in severe CVID patients.
    The Journal of Immunology 05/2014; · 5.36 Impact Factor

Full-text (3 Sources)

Available from
Aug 19, 2014