Syndecan-4 Mediates the Coinhibitory Function of DC-HIL on T Cell Activation

Abstract

Receptor-ligand interactions between APCs and T cells determine whether stimulation of the latter leads to activation or inhibition. Previously, we showed that dendritic cell-associated heparin sulfate proteoglycan-dependent integrin ligand (DC-HIL) on APC can inhibit T cell activation by binding an unknown ligand expressed on activated T cells. Because DC-HIL binds heparin/heparan sulfate and heparin blocks the inhibitory function of DC-HIL, we hypothesized that a heparin/heparan sulfate proteoglycan on activated T cells is the relevant ligand. Screening assays revealed that syndecan-4 (SD-4) is the sole heparan sulfate proteoglycan immunoprecipitated by DC-HIL from extracts of activated T cells and that blocking SD-4 abrogates binding of DC-HIL to activated T cells. Moreover, cell-bound SD-4 ligated by DC-HIL or cross-linked by anti-SD-4 Ab attenuated anti-CD3 responses, whereas knocked-down SD-4 expression led to enhanced T cell response to APC. Blockade of endogenous SD-4 using specific Ab or soluble SD-4 receptor led to augmented T cell reactions to syngeneic and allogeneic stimulation in vitro and exacerbated contact hypersensitivity responses in vivo. We conclude that SD-4 is the T cell ligand through which DC-HIL mediates its negative coregulatory function.

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

“…We also found DC-HIL to deliver a potent inhibitory signal to T cells, in an Ag-independent manner, by binding a heparin/heparan-like saccharide of syndecan-4 (SD-4) on activated T cells (19,20). These findings led us to hypothesize that DC-HIL binds microbial pathogens in a similar manner.…”

“…Similarly, we showed DC-HIL to bind a heparin/ heparan sulfate (HS)-like saccharide of SD-4 on activated T cells (20). We thus posited that DC-HIL may also recognize microbial pathogens through a similar sugar moiety.…”

“…Binding of DC-HIL to T. rubrum was blocked completely by addition of heparin (2 g/ml) (Fig. 2D), which we showed previously to inhibit DC-HIL binding to activated T cells (20). To sort the fungal ligands of DC-HIL, T. rubrum fungi were pretreated with N-glycosidase that removes saccharide residues from glycoproteins ( Fig.…”

Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation

“…On the other hand, this might also indicate a role of SDC4 for the function of other cell types. Indeed, activation-dependent upregulation of SDC4 was found in both, DCs and T cells 6,8 . It has been shown that depletion of SDC4 þ T cells suppressed CHS, an activated T-cell-driven disease 4 .…”

“…SDCs are transmembrane heparan sulfate proteoglycans interacting with growth factors and cytokines and a variety of extracellular matrix molecules via their heparan sulfate chains 5 . While SDC4 is ubiquitously expressed at low levels, an activation-dependent upregulation of SDC4 has been reported for macrophages, DCs and CD4 þ T cells [6][7][8] . SDC4 expression is often involved in migration and adhesion of various cells including DCs [9][10][11] .…”