Inhibition of T‐cell activation by syndecan‐4 is mediated by CD148 through protein tyrosine phosphatase activity

Abstract Most coinhibitory receptors regulate T‐cell responses through an ITIM that recruits protein tyrosine phosphatases (PTPs) to mediate inhibitory function. Because syndecan‐4 (SD‐4), the coinhibitor for DC‐associated heparan sulfate proteoglycan integrin ligand (DC‐HIL), lacks such an ITIM, we posited that SD‐4 links with a PTP in an ITIM‐independent manner. We show that SD‐4 associates constitutively with the intracellular protein syntenin but not with the receptor‐like PTP CD148 on human CD4 + T cells. Binding to DC‐HIL allowed SD‐4 to assemble with CD148 through the help of syntenin as a bridge, and this process upregulated the PTP activity of CD148, which is required for SD‐4 to mediate DC‐HIL's inhibitory function. Using a mouse model, we found SD‐4 to be located away from the immunological synapse formed between T cells and APCs during activation of T cells. These findings indicate that SD‐4 is unique among known T‐cell coinhibitors, in employing CD148 to inhibit T‐cell activation at a site distal from the synapse.