Syndecan-4 mediates the coinhibitory function of DC-HIL on T cell activation.
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.
Chung
Jin-Sung
JS
Department of Dermatology, University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, TX 75390, USA.
Dougherty
Irene
I
Cruz
Ponciano D
PD
Ariizumi
Kiyoshi
K
D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins; D005260:Female; D005786:Gene Expression Regulation; D006493:Heparin / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D053671:Syndecan-4; D006493:Heparin