title: CD47 signaling regulates the immunosuppressive activity of VEGF in T cells.
abstract: Thrombospondin-1 (TSP1) inhibits angiogenesis, in part, by interacting with the ubiquitous cell-surface receptor CD47. In endothelial cells, CD47 interacts directly with vascular endothelial growth factor receptor (VEGFR)-2, and TSP1 inhibits VEGFR2 phosphorylation and signaling by disrupting this association. We show that CD47 similarly associates with and regulates VEGFR2 in T cells. TSP1 inhibits phosphorylation of VEGFR2 and its downstream target Src in wild type but not in CD47-deficient human Jurkat and primary murine T cells. VEGFR2 signaling inhibits proliferation and TCR signaling in wild type T cells. However, ligation of CD47 by TSP1 or loss of CD47 expression reverses some inhibitory effects of VEGF on proliferation and T cell activation. We further found that VEGF and VEGFR2 expression are upregulated in CD47-deficient murine CD4(+) and human Jurkat T cells, and the resulting autocrine VEGFR2 signaling enhances proliferation and some TCR responses in the absence of CD47. Thus, CD47 signaling modulates the ability of VEGF to regulate proliferation and TCR signaling, and autocrine production of VEGF by T cells contributes to this regulation. This provides a mechanism to understand the context-dependent effects of TSP1 and VEGF on T cell activation, and reveals an important role for CD47 signaling in regulating T cell production of the major angiogenic factor VEGF.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982;
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982;
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chang
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20982; and.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Langston
authors.initials: L
authors.lastname: Lim
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Poonam
authors.initials: P
authors.lastname: Mannan
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Garfield
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pendrak
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982;
authors.forename: David R
authors.initials: DR
authors.lastname: Soto-Pantoja
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982;
authors.forename: Avi Z
authors.initials: AZ
authors.lastname: Rosenberg
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982;
authors.forename: Shelly
authors.initials: S
authors.lastname: Jin
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20982; droberts@helix.nih.gov.
authors.forename: David D
authors.identifier: http://orcid.org/0000-0002-2481-2981
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D051928:CD47 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007108:Immune Tolerance; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000276:immunology; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D019700:Thrombospondin 1 / Q000276:immunology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D011948:Receptors, Antigen, T-Cell; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases