title: 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.
authors.affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, TX, USA.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Chung
authors.forename: Ponciano D
authors.initials: PD
authors.lastname: Cruz
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ariizumi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D054992:Immunological Synapses; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053671:Syndecan-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053676:Syntenins / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D019812:Heparan Sulfate Proteoglycans; D034741:RNA, Small Interfering; D053671:Syndecan-4; D053676:Syntenins; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3