Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation.
Biological activities of the matrix glycoprotein thrombospondin-1 (TSP1) are cell type specific and depend on the relative expression or activation of several TSP1 receptors. Although engaging individual TSP1 receptors in T lymphocytes can elicit costimulating signals, in this study we show that intact TSP1 inhibits TCR-mediated T cell activation, assessed globally using cDNA microarrays. TSP1 signaling suppressed expression of several genes induced in Jurkat T cells, including the T cell activation markers CD69, early growth response gene-1 (Egr-1), and phosphatase of activated cells (PAC-1). TCR-stimulated and CD47-costimulated IL-2 secretion and cell surface CD69 expression were also inhibited by TSP1. The specific inhibitory effect of TSP1 was verified in freshly isolated human PBMCs. TSP1 inhibited TCR-mediated but not protein kinase C-mediated T cell activation. Using CD69 expression as a marker, we demonstrated that the inhibitory activity of TSP1 depended on two TSP1 receptors, CD47 and integrin-associated protein heparan sulfate proteoglycans. Signals from these receptors inhibited TCR signaling downstream of ZAP70, but upstream of NF-AT. Therefore, the expression of TSP1 induced during wound repair and in tumor stroma may limit T cell activation at these sites.
Li
Z
Z
Laboratory of Pathology, Division of Clinical Science, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
He
L
L
Wilson
K
K
Roberts
D
D
D020121:5' Untranslated Regions / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology; D001665:Binding Sites / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006023:Glycoproteins / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D019169:Jurkat Cells; D026563:LDL-Receptor Related Protein-Associated Protein; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D011493:Protein Kinase C / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology*
D020121:5' Untranslated Regions; D015703:Antigens, CD; D015415:Biomarkers; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D026563:LDL-Receptor Related Protein-Associated Protein; D011948:Receptors, Antigen, T-Cell; D019700:Thrombospondin 1; D006493:Heparin; D011493:Protein Kinase C