N-linked glycan modification on antigen-presenting cells restores an allospecific cytotoxic T cell response.
Neefjes J J,De Bruijn M L,Boog C J,Nieland J D,Boes J,Melief C J,Ploegh H L
The Journal of experimental medicine
The B6 anti-bm6 allospecific CTL response is strictly dependent on CD4+ cells when using LPS blasts as stimulator cells. Altering the N-linked carbohydrates on stimulator cells by use of the N-linked trimming glycosidase inhibitors 1-deoxymannojirimycin and swainsonine, or by treatment with bacterial neuraminidase, results in a restoration of the B6 anti-bm6 response in the absence of CD4+ cells. The extent of restoration is inversely correlated with the number of sialic acids present on N-linked glycans of stimulator cells.
10.1084/jem.171.2.583
Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells.
Walz G,Aruffo A,Kolanus W,Bevilacqua M,Seed B
Science (New York, N.Y.)
Endothelial leukocyte adhesion molecule-1 (ELAM-1) is an endothelial cell adhesion molecule that allows myeloid cells to attach to the walls of blood vessels adjacent to sites of inflammation. ELAM-1 recognizes the sialyl-Lewis X (sialyl-Lex) determinant, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc-, a granulocyte carbohydrate also found on the surface of some tumor cell lines. Binding of myeloid cells to soluble ELAM-1 is inhibited by a monoclonal antibody recognizing sialyl-Lex or by proteins bearing sialyl-Lex, some of which may participate in humoral regulation of myeloid cell adhesion. Stimulated granulocytes also release an inhibitor of ELAM-1 binding that can be selectively adsorbed by monoclonal antibody to sialyl-Lex.
10.1126/science.1701275
Antigen-presenting cells for CD8+ T cells.
Sprent J,Schaefer M
Immunological reviews
Evidence is presented that a wide variety of cell types are capable of presenting class I alloantigens to purified unprimed CD8+ cells in the absence of added help. These cells include dendritic cells, a population of Ia- Thy 1- cells in spleen, peritoneal exudate cells and one of three T-tumor lines. Some cell types, e.g. T-blast cells and overnight-adherent peritoneal exudate cells (OA-PEC) only expressed antigen-presenting cell (APC) function in the presence of added lymphokines. Stimulation of OA-PEC with small concentrations of lipopolysaccharide or treatment of T-blast cells with neuraminidase (N'dase) strongly enhanced the APC function of these cells and led to helper-independent responses. N'dase treatment of small resting T stimulators caused partial restoration of APC function: strong responses were observed but only in the presence of exogenous lymphokines. Studies with T-tumor lines preincubated with IFN-gamma suggested that APC function correlates closely with antigen (class I) expression. Collectively, the data support the view that APC function depends upon a multiplicity of factors including antigen density, the level of accessory (adhesion) molecules and net surface charge. It is suggested that the potency of APC function is largely a reflection of the overall avidity of T-APC interaction: high-avidity binding leads to helper-independent responses whereas weaker binding results in helper-dependent responses.
Sialoadhesin on macrophages: its identification as a lymphocyte adhesion molecule.
van den Berg T K,Brevé J J,Damoiseaux J G,Döpp E A,Kelm S,Crocker P R,Dijkstra C D,Kraal G
The Journal of experimental medicine
In this study we present evidence that the mouse and rat sialoadhesin (originally named sheep erythrocyte receptor) on macrophages can function as a lymphocyte adhesion molecule. Lymphocytes were shown to bind to the splenic marginal zone, and lymph node subcapsular sinus and medulla in a frozen section assay. Selective depletion experiments showed that binding was mediated by macrophages. Adhesion was blocked by preincubation of the sections with monoclonal antibodies against mouse or rat sialoadhesin. Binding was temperature dependent, divalent cation independent, and involved sialic acid residues on the lymphocyte, as it could be inhibited by prior neuraminidase treatment or addition of the ganglioside GD1a. Binding to sialoadhesin was confirmed using the purified receptor and was observed among T cells, T blasts, B cells, and B blasts. Isolated macrophages or dendritic cells showed little binding. Sialoadhesin provides the first example of a macrophage-restricted lymphocyte adhesion molecule.
10.1084/jem.176.3.647
Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis.
Science advances
Lysosomal exocytosis is a ubiquitous process negatively regulated by neuraminidase 1 (NEU1), a sialidase mutated in the glycoprotein storage disease sialidosis. In mice, excessive lysosomal exocytosis is at the basis of disease pathogenesis. Yet, the tissue-specific molecular consequences of this deregulated pathway are still unfolding. We now report that in muscle connective tissue, fibroblasts have features of myofibroblasts and are proliferative, migratory, and exocytose large amounts of exosomes. These nanocarriers loaded with activated transforming growth factor-β and wingless-related integration site (WNT)/β-catenin signaling molecules propagate fibrotic signals to other cells, maintaining the tissue in a prolonged transitional status. Myofibroblast-derived exosomes fed to normal fibroblasts convert them into myofibroblasts, changing the recipient cells' proliferative and migratory properties. These findings reveal an unexpected exosome-mediated signaling pathway downstream of NEU1 deficiency that propagates a fibrotic disease and could be implicated in idiopathic forms of fibrosis in humans.
10.1126/sciadv.aav3270
Targeted glycan degradation potentiates the anticancer immune response in vivo.
Nature chemical biology
Currently approved immune checkpoint inhibitor therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, most patients across cancer types still fail to respond. Consequently, there is interest in discovering and blocking alternative pathways that mediate immune suppression. One such mechanism is an upregulation of sialoglycans in malignancy, which has been recently shown to inhibit immune cell activation through multiple mechanisms and therefore represents a targetable glycoimmune checkpoint. Since these glycans are not canonically druggable, we designed an αHER2 antibody-sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells. In syngeneic breast cancer models, desialylation enhanced immune cell infiltration and activation and prolonged the survival of mice, an effect that was dependent on expression of the Siglec-E checkpoint receptor found on tumor-infiltrating myeloid cells. Thus, antibody-sialidase conjugates represent a promising modality for glycoimmune checkpoint therapy.
10.1038/s41589-020-0622-x