Cell Surface Heparan Sulfate Proteoglycans Influence MHC Class II-Restricted Antigen Presentation

Abstract

Heparan sulfate proteoglycans (HSPGs) are glycoproteins ubiquitously distributed on the cell surface and in the extracellular matrix. Their heparan sulfate moieties often represent alternative attachment points for extracellular proteins that target specific receptors. Thus, HSPGs modulate ligand-receptor encounters and participate in numerous biological processes. In this study, we examined whether HSPGs can also influence MHC class II-restricted Ag presentation. We selected a heparan sulfate ligand derived from the HIV-1 Tat protein and coupled it to a model protein Ag. We showed that coupling of the Tat fragment makes the Ag capable of binding cells, including APCs, and increases its ability to stimulate specific T cells up to 180-fold. The boosting effect depends on Ag processing; it vanished in the presence of an excess of heparin or free Tat fragment, indicating that HSPGs can behave as receptors involved in MHC class II processing and presentation. Furthermore, with FcγRII-bearing APCs, immune complexes containing the coupled Ag stimulated T cells up to 700-fold more efficiently than Ag-containing immune complexes. This effect vanished in the presence of heparin and is not found with FcγRII(-) APCs, indicating that HSPGs can also behave as coreceptors during FcγRIIR-mediated Ag presentation. These results indicate that ubiquitous receptors, such as HSPGs, can influence MHC class II-restricted Ag presentation and suggest that proteins will be supported more efficiently by the immune system if they have the inherent capacity to bind heparan sulfate.