title: CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions.
abstract: CD47 plays an important but incompletely understood role in the innate and adaptive immune responses. CD47, also called integrin-associated protein, has been demonstrated to associate in cis with β1 and β3 integrins. Here we test the hypothesis that CD47 regulates adhesive functions of T-cell α4β1 (VLA-4) and αLβ2 (LFA-1) in in vivo and in vitro models of inflammation. Intravital microscopy studies reveal that CD47(-/-) Th1 cells exhibit reduced interactions with wild-type (WT) inflamed cremaster muscle microvessels. Similarly, murine CD47(-/-) Th1 cells, as compared with WT, showed defects in adhesion and transmigration across tumor necrosis factor-α (TNF-α)-activated murine endothelium and in adhesion to immobilized intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-1) under flow conditions. Human Jurkat T-cells lacking CD47 also showed reduced adhesion to TNF-α-activated endothelium and ICAM-1 and VCAM-1. In cis interactions between Jurkat T-cell β2 integrins and CD47 were detected by fluorescence lifetime imaging microscopy. Unexpectedly, Jurkat CD47 null cells exhibited a striking defect in β1 and β2 integrin activation in response to Mn(2+) or Mg(2+)/ethylene glycol tetraacetic acid treatment. Our results demonstrate that CD47 associates with β2 integrins and is necessary to induce high-affinity conformations of LFA-1 and VLA-4 that recognize their endothelial cell ligands and support leukocyte adhesion and transendothelial migration.
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115 Harvard Medical School, Boston, MA 02115 Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63130 Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia, Porto Alegre 90010-395, Brazil Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 Division of Gastrointestinal Pathology, Emory University School of Medicine, Atlanta, GA 30322 Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Veronica
authors.initials: V
authors.lastname: Azcutia
authors.forename: Matthew
authors.initials: M
authors.lastname: Routledge
authors.forename: Marcie R
authors.initials: MR
authors.lastname: Williams
authors.forename: Gail
authors.initials: G
authors.lastname: Newton
authors.forename: William A
authors.initials: WA
authors.lastname: Frazier
authors.forename: Andrè
authors.initials: A
authors.lastname: Manica
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Croce
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.forename: Angela B
authors.initials: AB
authors.lastname: Schmider
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Turman
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Soberman
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D039041:Integrin alpha4beta1 / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
chemical_list: D051928:CD47 Antigen; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D014409:Tumor Necrosis Factor-alpha